Pyridazine, pyrimidine and pyrazine ethyne compounds

ABSTRACT

In accordance with the present invention, there is provided a novel class of heterocyclic compounds. Compounds of the invention contain a substituted, unsaturated five, six or seven membered heterocyclic ring that includes at least one nitrogen atom and at least one carbon atom. The ring additionally includes three, four or five atoms independently selected from carbon, nitrogen, sulfur and oxygen atoms. The heterocyclic ring has at least one substituent located at a ring position adjacent to a ring nitrogen atom. This mandatory substituent of the ring includes a moiety (B), linked to the heterocyclic ring via a carbon-carbon double bond, a carbon-carbon triple bond or an azo group. The mandatory substituent is positioned adjacent to the ring nitrogen atom. Invention compounds are capable of a wide variety of uses. For example heterocyclic compounds can act to modulate physiological processes by functioning as agonists and antagonists of receptors in the nervous system. Invention compounds may also act as insecticides, and as fungicides. Pharmaceutical compositions containing invention compounds also have wide utility.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 10/217,800 filed Aug. 13, 2002 now U.S. Pat. No. 6,774,138,which is a continuation-in-part of U.S. patent application Ser. No.09/387,073 filed Aug. 31, 1999, now abandoned.

FIELD OF INVENTION

The present invention relates to novel heterocyclic compounds whichcontain a heterocylic ring bearing at least one substituent, linkedtogether by a linker containing an alkyne group, an alkene group or anazo group. In addition, the present invention relates to pharmaceuticalcompositions containing novel invention compounds.

BACKGROUND OF THE INVENTION

Unsaturated heterocylic compounds find a wide variety of uses. Forexample, compounds of this class find uses as modulators ofphysiological processes that are mediated by ligand-activated receptorsReceptors that are activated by ligands are located throughout thenervous, cardiac, renal, digestive and bronchial systems, among others.Therefore, in the nervous system, for example, heterocyclic compoundsare capable of functioning as agonists or antagonists of receptors forneurotransmitters, neurohormones and neuromodulators. Ligand-activatedreceptors have been identified in a wide variety of species, includinghumans, other mammals and vertebrates as well as in invertebratespecies. Therefore, compounds of this class are also able to modulatereceptor-mediated processes throughout phylogeny and find uses in a widevariety of applications, e.g., as insecticides and fingicides.

Accordingly, there is a continuing need in the art for new members ofthis compound class.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a novelclass of heterocyclic compounds. Compounds of the invention contain asubstituted, unsaturated five, six or seven membered heterocyclic ringthat includes at least one nitrogen atom and at least one carbon atom.The ring additionally includes three, four or five atoms independentlyselected from carbon, nitrogen, sulfur and oxygen atoms. Theheterocyclic ring has at least one substituent located at a ringposition adjacent to a ring nitrogen atom. This mandatory substituent ofthe ring includes a moiety (B), linked to the heterocyclic ring via acarbon-carbon double bond, a carbon-carbon triple bond or an azo group.The mandatory substituent is positioned adjacent to the ring nitrogenatom.

Invention compounds are useful for a wide variety of applications. Forexample heterocyclic compounds can act to modulate physiologicalprocesses by functioning as agonists and antagonists of receptors in thenervous system. Invention compounds may also act as insecticides, and asfungicides. Pharmaceutical compositions containing invention compoundsalso have wide utility.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided compoundshaving the structure:A-L-Bor enantiomers, diastereomeric isomers or mixtures of any two or morethereof, or pharmaceutically acceptable salts thereof, wherein:

A is a 5-, 6- or 7-membered ring having the structure:

wherein at least one of W, X, Y and Z is (CR)_(p), wherein p is 0, 1 or2;

the remainder of W, X, Y and Z are each independently O, N or S; and

each R is independently halogen, substituted or unsubstitutedhydrocarbyl, substituted or unsubstituted aryl, heterocycle, mercapto,nitro, carboxyl, carbamate, carboxamide, hydroxy, ester, cyano, amine,amide, amidine, amido, sulfonyl or sulfonamide, wherein q is 0, 1, 2 or3;

L is substituted or unsubstituted alkenylene, alkynylene, or azo; and

B is substituted or unsubstituted hydrocarbyl, substituted orunsubstituted cyclohydrocarbyl, substituted or unsubstitutedheterocycle, optionally containing one or more double bonds, orsubstituted or unsubstituted aryl;

provided, that the following compounds are excluded:

the compounds wherein A is a 6-membered ring wherein: W, X, Y and Z are(CR)p wherein p is 1; and R at the W position is hydrogen, lower alkyl,hydroxy, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-loweralkyl, di-lower alklamino-lower alkyl, unsubstituted orhydroxy-substituted lower alkyleneamino-lower alkyl, lower alkoxy, loweralkanoyloxy, amino-lower alkoxy, lower alkylamino-lower alkoxy, di-loweralkylamino-lower alkoxy, phthalimido-lower alkoxy, unsubstituted orhydroxy- or 2-oxo-imidazolidin-1-yl-substitued lower alkyleneamino-loweralkoxy, carboxy, esterified or amidated carboxy, carboxy-lower alkoxy oresterified carboxy-lower-alkoxy;

R at the X position is hydrogen; R at the Y position is hydrogen, loweralkyl, carboxy, esterified carboxy, amidated carboxy, hydroxy-loweralkyl, hydroxy, lower alkoxy or lower alkanoyloxy; and R at the Zposition is hydrogen, lower alkyl, hydroxy-lower alkyl, carboxy,esterified carboxy, amidated carboxy, unsubstituted or lower alkyl-,lower alkoxy-, halo- and/or trifluoromethyl-substituted N-loweralkyl-N-phenylcarbamoyl, lower alkoxy, halo-lower alkyl or halo-loweralkoxy; L is substituted or unsubstituted alkenylene, alkynylene or azo;B is substituted or unsubstituted aryl or heterocycle having two or moredouble bonds, wherein substituents are independently lower alkyl, loweralkenyl, lower alkynyl, phenyl, phenyl-lower alkynyl, hydroxy,hydroxy-lower alkyl, lower alkoxy, lower alkenyloxy, loweralkylenedioxy, lower alkanoyloxy, phenoxy, phenyl-lower alkoxy, acyl,carboxy, esterified carboxy, amidated carboxy, cyano, nitro, amino,acylamino, N-acyl-N-lower alkylamino, halo and halo-lower alkyl, whereinphenyl, phenyl-lower alkynyl, phenoxy, and phenyl-lower alkoxy may bearfurther substituents; and

the compounds wherein A is a 6-membered ring wherein: W, X, Y and Z are(CR)p wherein p is 1; R at the X position is not hydrogen; and R at theW, Y and Z positions are hydrogen; L is alkenylene or alkynylene; and Bis a substituted or unsubstituted aryl or heterocycle containing two ormore double bonds;

the compounds wherein A is a 5-membered ring wherein: one of W, X, Y andZ is (CR)p, and p is 0, two of W, X, Y and Z are (CR)p and p is 1, andthe remaining variable ring member is O or S; or one of W, X, Y and Z isN, one of W, X, Y and Z is (CR)p and p is 1, one of W, X, Y and Z is(CR)p and p is 0, and the remaining variable ring member is O, S or(CR)p, and p is 1; or two of W, X, Y and Z are N, one of W, X, Y and Zis (CR)p, and p is 0, and the remaining variable ring member is, O or Sor (CR)p, and p is 1; each R is independently hydrogen, nitro, halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylthio, C₁-C₄-haloalkylthio, C₃-C₆-alkenyl or C₃-C₈-cycloalkyl;L is alkynylene; and B is substituted or unsubstituted aryl, whereinsubstituents are independently nitro, cyano, C₁-C₆-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkthio,C₁-C₄-haloalkylthio, C₁-C₄-alkoxycarbonyl, C₃-C₆-alkenyl, phenyl orphenoxy, wherein phenyl and phenoxy may bear further substituents; and

the compounds wherein A is a 6-membered ring wherein: W, X, Y and Z are(CR)p, wherein p is 1 and R is hydrogen; L is alkynylene; and B isunsubstituted 1-cyclopenten-1-yl or unsubstituted 1-cyclohexen-1-yl;

the compounds wherein A is a 5-membered ring wherein: W is (CR)p, and pis 0, Y and Z are (CR)p, and p is 1, X is N or S; and R is phenyl; or Wis (CR)p, and p is 0, X and Z are (CR)p, and p is 1, Y is O, N or S; andR is phenyl; L is unsubstituted alkenylene and B is unsubstitutedphenyl;

the compounds wherein A is a 5-membered ring containing two doublebonds, wherein one of W, X, Y and Z is (CR)_(p), and p is 0, and theremaining ring members are (CR)_(p) and p is 1;

and the compounds wherein A is unsubstituted heterocycle containing twoor more double bonds; L is alkenylene or alkynylene, and B isunsubstituted phenyl.

As employed herein, “hydrocarbyl” refers to straight or branched chainunivalent and bivalent radicals derived from saturated or unsaturatedmoieties containing only carbon and hydrogen atoms, and having in therange of about 1 up to 12 carbon atoms. Exemplary hydrocarbyl moietiesinclude alkyl moieties, alkenyl moieties, dialkenyl moieties, trialkenylmoieties, alkynyl moieties, alkadiynal moieties, alkatriynal moieties,alkenyne moieties, alkadienyne moieties, aLkenediyne moieties, and thelike. The term “substituted hydrocarbyl” refers to hydrocarbyl moietiesfurther bearing substituents as set forth below;

“alkyl” refers to straight or branched chain alkyl radicals having inthe range of about 1 up to 12 carbon atoms; “substituted alkyl” refersto alkyl radicals further bearing one or more substituents such ashydroxy, alkoxy, mercapto, aryl, heterocycle, halogen, trifluoromethyl,pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amide, amidine,amido, carboxyl, carboxamide, carbamate, ester, sulfonyl, sulfonamide,and the like;

“alkenyl” refers to straight or branched chain hydrocarbyl radicalshaving at least one carbon-carbon double bond, and having in the rangeof about 2 up to 12 carbon atoms (with radicals having in the range ofabout 2 up to 6 carbon atoms presently preferred), and “substitutedalkenyl” refers to alkenyl radicals further bearing one or moresubstituents as set forth above;

“alkenylene” refers to straight or branched chain divalent alkenylmoieties having at least one carbon-carbon double bond, and having inthe range of about 2 up to 12 carbon atoms (with divalent alkenylmoieties having in the range of about 2 up to 6 carbon atoms presentlypreferred), and “substituted lower alkenylene” refers to divalentalkenyl radicals further bearing one or more substituents as set forthabove;

“alkynyl” refers to straight or branched chain hydrocarbyl radicalshaving at least one carbon-carbon triple bond, and having in the rangeof about 2 up to 12 carbon atoms (with radicals having in the range ofabout 2 up to 6 carbon atoms presently being preferred), and“substituted alkynyl” refers to alkynyl radicals further bearing one ormore substituents as set forth above;

“alkynylene” refers to straight or branched chain divalent alkynylmoieties having at least one carbon-carbon triple bond, and having inthe range of about 2 up to 12 carbon atoms (with divalent alkynylmoieties having two carbon atoms presently being preferred), and“substituted alkynylene” refers to divalent alkynyl radicals furtherbearing one or more substituents as set forth above;

“cyclohydrocarbyl” refers to cyclic (i.e., ring-containing) univalentradicals derived from saturated or unsaturated moieties containing onlycarbon and hydrogen atoms, and having in the range of about 3 up to 20carbon atoms. Exemplary cyclohydrocarbyl moieties include cycloalkylmoieties, cycloalkenyl moieties, cycloalkadienyl moieties,cycloalkatrienyl moieties, cycloalkynyl moieties, cycloalkadiynylmoieties, spiro hydrocarbon moieties wherein two rings are joined by asingle atom which is the only common member of the two rings (e.g.,spiro[3.4]octanyl, and the like), bicyclic hydrocarbon moieties whereintwo rings are joined and have two atoms in common (e.g., bicyclo[3.2.1]octane, bicyclo [2.2.1]hept-2-ene, and the like), and the like.The term “substituted cyclohydrocarbyl” refers to cyclohydrocarbylmoieties further bearing one or more substituents as set forth above;

“cycloalkyl” refers to ring-containing radicals containing in the rangeof about 3 up to 20 carbon atoms, and “substituted cycloalkyl” refers tocycloalkyl radicals further bearing one or more substituents as setforth above;

“cycloalkenyl” refers to ring-containing alkenyl radicals having atleast one carbon-carbon double bond in the ring, and having in the rangeof about 3 up to 20 carbon atoms, and “substituted cycloalkenyl” refersto cyclic alkenyl radicals further bearing one or more substituents asset forth above;

“cycloalkynyl” refers to ring-containing alkynyl radicals having atleast one carbon-carbon triple bond in the ring, and having in the rangeof about 3 up to 20 carbon atoms, and “substituted cycloalkynyl” refersto cyclic alkynyl radicals further bearing one or more substituents asset forth above;

“aryl” refers to mononuclear and polynuclear aromatic radicals having inthe range of 6 up to 14 carbon atoms, and “substituted aryl” refers toaryl radicals further bearing one or more substituents as set forthabove, for example, alkylaryl moieties;

“heterocycle” refers to ring-containing radicals having one or moreheteroatoms (e.g., N, O, S) as part of the ring structure, and having inthe range of 3 up to 20 atoms in the ring. Heterocyclic moieties may besaturated or unsaturated when optionally containing one or more doublebonds, and may contain more than one ring. Heterocyclic moietiesinclude, for example, monocyclic moieties such as imidazolyl moieties,pyrimidinyl moieties, isothiazolyl moieties, isoxazolyl moieties,moieties, and the like, and bicyclic heterocyclic moieties such asazabicycloalkanyl moieties, oxabicycloalkyl moieties, and the like. Theterm “substituted heterocycle” refers to heterocycles further bearingone or more substituents as set forth above;

“azo” refers to the bivalent moiety—N.dbd.N—, wherein each bond isattached to a different carbon atom;

“halogen” refers to fluoride, chloride, bromide or iodide radicals.

In accordance with the present invention, A is a 5-, 6- or 7-memberedunsaturated heterocyclic moiety, containing a ring having at least onenitrogen atom located on the ring in a position adjacent to a carbonatom which bears a linking moiety as a substituent. The ring furthercontains 3, 4 or 5 independently variable atoms selected from carbon,nitrogen, sulfur and oxygen. Thus, A can be pyridinyl, imidazolyl,pyridazinyl, pyrimidinyl, pyrazoyl, pyrazinyl, triazolyl, triazinyl,tetrazolyl, tetrazinyl, isoxazolyl, oxazolyl, oxadiazolyl, oxatriazolyl,oxadiazinyl, isothiazolyl, thiazoyl, dioxazolyl, oxathiazolyl,oxathiazinyl, azepinyl, diazepinyl, and the like. Those of skill in theart will recognize that multiple isomers exist for a single chemicalformula; each of the possible isomeric forms of the various empiricalformulae set forth herein are contemplated by the invention. When avariable ring atom is carbon, it bears a hydrogen, or is optionallysubstituted with halogen, substituted or unsubstituted hydrocarbyl,substituted or unsubstituted aryl, thiol, nitro, carboxyl, ester, cyano,amine, amide, carboxamide, amidine, amido, sulfonamide, and the like,with presently preferred embodiments having no substituent (.i.e., q is0) or bearing the following substituents: halogen, alkyl, containing oneup to four carbon atoms, fluorinated alkyl, containing one up to fourcarbon atoms, and amine. Substitution at position Z of the ring ispresently preferred.

In accordance with one embodiment of the invention, A is a 5-, 6- or7-membered ring containing, as ring members, a nitrogen atom and asulfur atom. Moieties contemplated for use by this embodiment of theinvention include those wherein A is isothiazol-3-yl (1,2-thiazol-3-yl),thiazol-4-yl (1,3,-thiazol-4-yl), thiazol-2-yl (1,3-thiazol-2-yl),1,2-thiazin-3-yl, 1,3-thiazin-4-yl, 1,4-thiazin-3-yl, 1,3-thiazin-2-yl,thiazepinyl, and the like. Presently preferred moieties include thosewherein A is isothiazol-3-yl (1,2-thiazol-3-yl), thiazol-4-yl(1,3-thiazol-4-yl) and thiazol-2-yl (1,3-thiazol-2yl).

In accordance with another embodiment of the invention, A is a 5-, 6- or7-membered ring containing, as ring members, a nitrogen atom and anoxygen atom. Moieties contemplated by this embodiment of the inventioninclude those wherein A is 1,2-oxazin-3-yl, 1,3-oxazin-4-yl,1,4-oxazin-3-yl, 1,3-oxazin-2-yl, oxazol-2-yl, isoxazol-3-yl,oxazol-4-yl, oxazepinyl, and the like. Presently preferred moietiesinclude those wherein A is oxazol-2-yl, isoxazol-3-yl and oxazol-4-yl.

In accordance with another embodiment of the invention, A is a 5-, 6-,or 7-membered ring containing as ring members two nitrogen atoms.Moieties contemplated by this embodiment of the invention include thosewherein A is 3-pyridazinyl (1,2-diazin-3-yl), pyrimidin-4-yl(1,3-diazin-4-yl), pyrazin-3-yl (1,4-diazin-3-yl), pyrimidin-2-yl(1,3-diazin-2-yl), pyrazol-3-yl (1,2-diazol-3-yl), imidazol-4-yl(1,3-isodiazol-4-yl, imidazol-2-yl (1,3-isodiazol-2-yl), diazepinyl, andthe like. Presently preferred moieties include those wherein A is3-pyridazinyl (1,2-diazin-3-yl), pyrimidin-4-yl (1,3-diazin-4-yl),pyrazin-3-yl (1,4-diazin-3-yl), pyrimidin-2-yl (1,3-diazin-2-yl),1,3-isodiazol-4-yl and 1,3-isodiazol-2-yl.

In accordance with still another embodiment of the invention, A is a 5-,6-, or 7-membered ring containing, as ring members, three nitrogenatoms. Moieties contemplated by this embodiment of the invention includethose wherein A is 1,2,3-triazin-4-yl, 1,2,4-triazin-6-yl,1,2,4-triazin-3-yl, 1,2,4-triazin5-yl, 1,3,5-triazin-2-yl,1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, triazepinyl, and the like.Presently preferred moieties include those wherein A is1,2,3-triazin-4-yl, 1,2,4-triazin-6-yl, 1,2,4-triazin-6-yl,1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,3,5-triazin-2-yl,1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl.

In accordance with still another embodiment of the invention, A is a 5-,6-, or 7-membered ring containing, as ring members, four nitrogen atoms.Moieties contemplated for use in the practice of the invention includethose wherein A is tetrazin-2-yl, tetrazin-3-yl, tetrazin-5-yl,tetrazolyl, tetrazepinyl, and the like. Presently preferred moietiesinclude those wherein A is tetrazolyl.

In accordance with yet another embodiment of the invention, A is a 5-,6-, or 7-membered ring containing, as ring members, one sulfur atom andtwo nitrogen atoms. Moieties contemplated by this embodiment of theinvention include those wherein A is 1,2,6-thiadiazin-3-yl,1,2,5-thiadiazin-3-yl, 1,2,4-thiadiazin-3-yl, 1,2,5-thiadiazin-4-yl,1,2,3-thiadiazin-4-yl, 1,3,4-thiadiazin-5-yl, 1,3,4-thiadiazin-2-yl,1,2,4-thiadiazin-5-yl, 1,3,5-thiadiazin-4-yl, 1,3,5-thiadiazin-2-yl,1,2,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, thiadiazepinyl, and thelike. Presently preferred moieties include those wherein A is1,2,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl,1,2,5-thiadiazol-3-yl and 1,2,4-thiadiazol-5-yl.

In accordance with yet another embodiment of the invention, A is a 5-,6-, or 7-membered ring containing, as ring members, one oxygen atom andtwo nitrogen atoms. Moieties contemplated by this embodiment of theinvention include those wherein A is 1,2,6-oxadiazin-3-yl,1,2,5-oxadiazin-3-yl, 1,2,4-oxadiazin-3-yl, 1,2,5-oxadiazin-4-yl,1,2,3-oxadiazin-4-yl, 1,3,4-oxadiazin-5-yl, 1,3,4-oxadiazin-2-yl,1,2,4-oxadiazin-5-yl, 1,3,5-oxadiazin-4-yl, 1,3,5-oxadiazin-2-yl,1,2,4-oxadiazol-3-yl 1,2,3-oxadiazol-4-yl, 1,3,4-oxadiazol-2-yl,1,2,5-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, oxadiazepinyl, and the like.Presently preferred moieties include those wherein A is1,2,4-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,3,4-oxadiazol-2-yl,1,2,5-oxadiazol-3-yl and 1,2,4-oxadiazol-5-yl.

In accordance with still another embodiment of the invention, A is a 5-,6-, or 7-membered ring containing as ring members, one up to sixnitrogen atoms, and/or one up to six carbon atoms, and/or zero up tofive sulfur atoms, and/or zero up to five oxygen atoms.

Further, in accordance with the present invention, L is a linking moietywhich links moieties A and B. L is selected from substituted orunsubstituted alkenylene moieties, alkynylene moieties or azo moieties.Presently preferred compounds of the invention are those wherein L isalkenylene or alkynylene moieties containing two carbon atoms, withalkynylene most preferred.

Further, in accordance with the present invention, B is a moiety linkedthrough bridging moiety L to moiety A. Radicals contemplated for use inthe invention are those wherein B is substituted or unsubstitutedhydrocarbyl, substituted or unsubstituted cyclohydrocarbyl, substitutedor unsubstituted heterocycle, optionally containing one or more doublebonds, substituted or unsubstituted aryl, and the like.

Presently preferred compounds of the invention are those wherein B is asubstituted or unsubstituted hydrocarbyl selected from substituted orunsubstituted alkyl moieties, alkenyl moieties, dialkenyl moieties,trialkenyl moieties, alkynyl moieties, alkadiynyl moieties, alkatriynylmoieties, alkenynyl moieties, alkadienynyl moieties, alkenediynylmoieties, and the like.

Further preferred compounds of the invention are those wherein B is asubstituted or unsubstituted cyclohydrocarbyl selected from substitutedor unsubstituted cycloalkyl moieties, cycloalkenyl moieties,cycloalkadienyl moieties, cycloalkatrienyl moieties, cycloalkynylmoieties, cycloalkadiynyl moieties, bicyclic hydrocarbon moietieswherein two rings have two atoms in common, and the like. Especiallypreferred compounds are those wherein B is cycloalkyl and cycloalkenylhaving in the range of 4 up to about 8 carbon atoms.

Still further preferred compounds of the invention are those wherein Bis a substituted or unsubstituted heterocycle, optionally containing oneor more double bonds. Exemplary compounds include pyridyl, thiazolyl,furyl, dihydropyranyl, dihydrothiopyranyl, piperidinyl, and the like.Also preferred are compounds wherein B is substituted or unsubstitutedaryl. Especially preferred compounds are those wherein substituents aremethyl, trifluoromethyl and fluoro and wherein B is3,5-di-trifluoromethyl phenyl.

Those of skill in the art recognize that invention compounds may containone or more chiral centers, and thus can exist as racemic mixtures. Formany applications, it is preferred to carry out stereoselectivesyntheses and/or to subject the reaction product to appropriatepurification steps so as to produce substantially optically purematerials. Suitable stereoselective synthetic procedures for producingoptically pure materials are well known in the art, as are proceduresfor purifying racemic mixtures into optically pure fractions. Those ofskill in the art will further recognize that invention compounds mayexist in polymorphic forms wherein a compound is capable ofcrystallizing in different forms. Suitable methods for identifying andseparating polymorphisms are known in the art.

As used herein, with reference to compounds not embraced by the scope ofthe claims, esterified carboxy is, for example, lower alkoxycarbonyl,phenyl-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl substitutedin the phenyl moiety by one or more substituents selected from loweralkyl, lower alkoxy, halo and halo-lower alkyl. Esterifiedcarboxy-lower-alkoxy is, for example, lower alkoxycarbonyl-lower alkoxy.Amidated carboxy is, for example, unsubstituted or aliphaticallysubstituted carbamoyl such as carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl unsubstituted or lower alkyl-, loweralkoxy-, halo- and/or trifluoromethyl-substituted N-phenyl- orN-lower-alkyl-N-phenyl-carbamoyl.

As used herein, with reference to compounds not embraced by the scope ofthe claims, acyl is, for example, lower alkanoyl, lower alkenoyl orunsubstituted or lower alkyl-, lower alkoxy-, halo- and/ortrifluoromethyl-substituted benzoyl. Acylamino is, for example, loweralkanoylamino, and N-acyl-N-lower alkylamino is, for example, N-loweralkanoyl-N-lower-alkylamino or unsubstituted or lower alkyl-, loweralkoxy-halo- and/or trifluoromethyl-substituted benzoylamino.

As referred to in reference to compounds not embraced by the scope ofthe claims “lower” groups are understood to comprise up to and includingseven carbon atoms. N-lower-alkyl-N-phenylcarbamoyl is, for example,N—C₁-C₄alkyl-N-phenylcarbamoyl, such as N-methyl, N-ethyl, N-propyl,N-isopropyl or N-butyl-N-phenylcarbamoyl.

As used herein, with reference to compounds not embraced by the scope ofthe claims, amino-lower alkyl is, for example, amino-C₁-C₄alkyl,preferably of the formula —(CH₂)_(n),—NH₂ in which n is 2 or 3, such asaminomethyl, 2-aminoethyl, 3-aminopropyl or 4-aminobutyl. Hydroxy-loweralkyl is, for example, hydroxy-C₁-C₄alkyl, such as hydroxymethyl,2-hydroxy ethyl, 3-hydroxypropyl, 2-hydroxyisopropyl or 4-hydroxybutyl.Halo-lower alkyl is, for example, polyhalo-C₁-C₄alkyl, such astrifluoromethyl.

As used herein, with reference to compounds not embraced by the scope ofthe claims, lower alkoxy is, for example, C₁-C₇alkoxy, preferablyC₁-C₄alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy orbutyloxy, but may also represent isobutyloxy, sec.butyloxy,tert.-butyloxy or a C₅-C₇alkoxy group, such as a pentyloxy, hexyloxy orheptyloxy group amino-lower alkoxy is, for example, amino-C₂-C₄alkoxypreferably of the formula —O—(CH₂)_(n)—NR_(a)R_(b) in which n is 2 or 3,such as 2-aminoethoxy, 3-aminopropyloxy or 4-aminobutyloxy.Carboxy-lower-alkoxy is, for example, carboxy-C₁-C₄alkoxy, such ascarboxymethoxy, 2-carboxyethoxy, 3-carboxypropyloxy or4-carboxybutyloxy. Lower alkanoyloxy is, for example, C₁-C₇alkanoyloxy,such as acetoxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy.Halo-lower alkoxy is, for example, halo- or polyhalo-C₁-C₇alkoxy,preferably halo- or polyhalo-C₁-C₄alkoxy, such as halo- orpolyhaloethoxy, halo- or polyhalopropyloxy or butyl-oxy, wherein “poly”refers, for example, to tri- or pentahalo, and “halo” denotes, forexample, fluoro or chloro.

As used herein, with reference to compounds not embraced by the scope ofthe claims, lower alkylamino-lower alkoxy is, for example,C₁-C₄alkylamino-C₂-C₄alkoxy, preferably of theformula—O—(CH₂)_(n)—NR_(a)R_(b) in which n is 2 or 3 and R_(a) andR_(b), independently of each other, denote lower alkyl groups as definedhereinbefore, such as methyl, ethyl, propyl or butyl. Loweralkylamino-lower alkyl is, for example, C₁-C₄alkylamino-C-₁-C₄alkyl,preferably of the formula —(CH₂)_(n)—NR— aR_(b) in which n is 2 or 3 andR_(a) and R_(b), independently of each other, denote lower alkyl groupsas defined hereinbefore, such as methyl, ethyl, propyl or butyl.Di-lower alkylamino-lower alkyl is, for example,Di-C₁-C₄alkylamino-C₁-C₄alkyl, preferably of the formula—(CH₂)_(n)—NR_(a)P_(b) in which n is 2 or 3 and R_(a) and R_(b),independently of each other, denote lower alkyl groups such as methyl,ethyl, propyl or butyl. Di-lower alkylamino-lower alkoxy is, forexample, Di-C₁-C₄alkylamino-C₂-C₄alkox-y, preferably of the formula—O—(CH₂)_(n)—NR_(a)R_(b) in which n is 2 or 3 and R_(a) and R_(b),independently of each other, denote lower alkyl groups such as methyl,ethyl, propyl or butyl.

As used herein, with reference to compounds not embraced by the scope ofthe claims, optionally hydroxy-substituted lower alkyleneamino-loweralkyl is, for example, unsubstituted or hydroxy-substituted 5- to7-membered alkyleneamino-C₁-C₄alkyl, preferably of the formula—(CH₂)_(n)—R_(c) in which n is 2 or 3 and Rc pyrrolidino,hydroxypyrrolidino, piperidino, hydroxypiperidino, homopiperidino orhydroxyhomopiperidino. Furthermore, optionally hydroxy-substituted loweralkyleneamino-lower alkoxy is, for example, unsubstituted orhydroxy-substituted 5- to 7-membered alkyleneamino-C₁-C₄alkoxy,preferably of the formula —O—(CH₂)_(n)—R_(c) in which n is 2 or 3 andR_(c) pyrrolidino, hydroxypyrrolidino, piperidino, hydroxypiperidino,homopiperidino or hydroxyhomopiperidino.

In accordance with another embodiment of the present invention, thereare provided pharmaceutical compositions comprising heterocycliccompounds as described above, in combination with pharmaceuticallyacceptable carriers. Optionally, invention compounds can be convertedinto non-toxic acid addition salts, depending on the substituentsthereon. Thus, the above-described compounds (optionally in combinationwith pharmaceutically acceptable carriers) can be used in themanufacture of medicaments useful for the treatment of a variety ofindications. Pharmaceutically acceptable carriers contemplated for usein the practice of the present invention include carriers suitable forintravenous, subcutaneous, transcutaneous, intramuscular,intracutaneous, intrathecal, inhalation, intracranial, epidural,vaginal, oral, sublingual, rectal, and the like administration.Administration in the form of creams, lotions, tablets, dispersiblepowders, granules, syrups, elixirs, sterile aqueous or non-aqueoussolutions, suspensions or emulsions, patches, and the like, iscontemplated.

For the preparation of oral liquids, suitable carriers includeemulsions, solutions, suspensions, syrups, and the like, optionallycontaining additives such as wetting agents, emulsifying and suspendingagents, sweetening, flavoring and perfuming agents, and the like.

For the preparation of fluids for parenteral administration, suitablecarriers include sterile aqueous or non-aqueous solutions, suspensions,or emulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms may also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They may be sterilized, for example,by filtration through a bacteria-retaining filter, by incorporatingsterilizing agents into the compositions, by irradiating thecompositions, or by heating the compositions. They can also bemanufactured in the form of sterile water, or some other sterileinjectable medium immediately before use.

Invention compounds can optionally be converted into non-toxic acidaddition salts. Such salts are generally prepared by reacting thecompounds of this invention with a suitable organic or inorganic acid.Representative salts include hydrochloride, hydrobromide, sulfate,bisulfate, methanesulfonate, acetate, oxalate, adipate, alginate,aspartate, valerate, oleate, laurate, borate, benzoate, lactate,phosphate, toluenesulfonate (tosylate), citrate, malate, maleate,fumarate, succinate, tartrate, napsylate, methanesulfonate,2-naphthalenesulfonate, nicotinate, benzenesulfonate, butyrate,camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,dodecylsulfate, glucoheptanoate, glycerophosphate, heptanoate,hexanoate, undecanoate, 2-hydroxyethanesulfonate, ethanesulfonate, andthe like. Salts can also be formed with inorganic acids such as sulfate,bisulfate, hemisulfate, hydrochloride, chlorate, perchlorate,hydrobromide, hydroiodide, and the like. Examples of a base salt includeammonium salts; alkali metal salts such as sodium salts, potassiumsalts, and the like; alkaline earth metal salts such as calcium salts,magnesium salts, and the like; salts with organic bases such asdicyclohexylamine salts, N-methyl-D-glucamine, phenylethylamine, and thelike; and salts with amino acids such as arginine, lysine, and the like.Such salts can readily be prepared employing methods well known in theart.

In accordance with another embodiment of the present invention, thereare provided methods for the preparation of heterocyclic compounds asdescribed above. For example, many of the heterocyclic compoundsdescribed above can be prepared using synthetic chemistry techniqueswell known in the art (see Comprehensive Heterocyclic Chemistry,Katritzky, A. R. and Rees, C. W. eds., Pergamon Press, Oxford, 1984)from a precursor of the substituted heterocycle of Formula 1 as outlinedin Scheme 1.

Thus in Scheme 1, a substituted heterocycle precursor (prepared usingsynthetic chemistry techniques well known in the art) is reacted with analkyne derivative. In Scheme 1, (R)_(q), W, X, Y, Z and B are as definedabove and D and E are functional groups which are capable of undergoinga transition metal-catalyzed cross-coupling reaction. For example, D isa group such as hydrogen, halogen, acyloxy, fluorosulfonate,trifluoromethanesulfonate, alkyl- or arylsulfonate, alkyl- orarylsulfinate, alkyl- or arylsulfide, phosphate, phosphinate and thelike, and E is hydrogen or a metallic or metalloid species such as Li,MgHal, SnR₃, B(OR)₂, SiR₃, GeR₃, and the like. The coupling may bepromoted by a homogeneous catalyst such as PdCl₂(PPh₃)₂, or by aheterogeneous catalyst such as Pd on carbon in a suitable solvent (e.g.THF, DME, MeCN, DMF etc.). Typically a co-catalyst such as copper (I)iodide and the like and a base (e.g. NEt₃, K₂CO₃ etc.) will also bepresent in the reaction mixture. The coupling reaction is typicallyallowed to proceed by allowing the reaction temperature to warm slowlyfrom about 0° C. up to ambient temperature over a period of severalhours. The reaction mixture is then maintained at ambient temperature,or heated to a temperature anywhere between 30° C. to 150° C. Thereaction mixture is then maintained at a suitable temperature for a timein the range of about 4 up to 48 hours, with about 12 hours typicallybeing sufficient. The product from the reaction can be isolated andpurified employing standard techniques, such as solvent extraction,chromatography, crystallization, distillation and the like.

Another embodiment of the present invention is illustrated in Scheme 2.A substituted heterocycle precursor is reacted with an alkene derivativein a manner similar to the procedure described for Scheme 1.

The product alkene derivative from Scheme 2 may be converted to analkyne derivative using the approach outlined in Scheme 3. Thus, thealkene derivative may be contacted with a halogenating agent such aschlorine, bromine, iodine, NCS, NBS, NIS, ICI etc. in a suitable solvent(CCl₄, CHCl₃, CH₂Cl₂, AcOH and the like). The resulting halogenatedderivative (G=halogen) is then treated with a suitable base such asNaOH, KOH, DBU, DBN, DABCO and the like which promotes doubleelimination reaction to afford the alkyne. The reaction is carried outin a suitable solvent such as EtOH, MeCN, toluene etc. at an appropriatetemperature, usually between 0° C. and 150° C.

In another embodiment of the present invention, a substitutedheterocyclic derivative is reacted with an aldehyde or ketone to providea substituted alkene. Thus in Scheme 4, J is hydrogen, PR₃, P(O)(OR)₂,SO₂R, SiR₃ and the like, K is hydrogen, lower alkyl or aryl (as definedpreviously) and R is hydrogen, Ac and the like. Suitable catalysts forthis reaction include bases such as NaH, nBuLi, LDA, LiHMDS, H₂NR, HNR₂,NR₃ etc., or electropositive reagents such as Ac₂O, ZnCl₂ and the like.The reaction is carried out in a suitable solvent (THF, MeCN etc.) at anappropriate temperature, usually between 0° C. and 150° C. Sometimes anintermediate is isolated and purified or partially purified beforecontinuing through to the alkene product.

In yet another embodiment of the present invention, a substitutedheterocyclic aldehyde or ketone is reacted with an activatedmethylene-containing compound to provide a substituted alkene. Thus inScheme 5, J, K, R, the catalyst and reaction conditions are as describedfor Scheme 4. Again, as in Scheme 4, sometimes an intermediate isisolated and purified or partially purified before continuing through tothe alkene product.

The alkene products from the reactions in Scheme 4 and Scheme 5 may beconverted to an alkyne derivative using reagents and conditions asdescribed for Scheme 3.

Another method for the preparation of heterocyclic compounds of FormulaI is depicted in Scheme 6.

In Scheme 6, Y is O or S and G is halogen or a similar leaving group, Land B are as defined previously. The reagents are contacted in asuitable solvent such as EtOH, DMF and the like and stirred until theproduct forms. Typically reaction temperatures will be in the range ofambient through to about 150° C., and reaction times will be from 1 h toabout 48 h, with 70° C. and 4 h being presently preferred. Theheterocycle product can be isolated and purified employing standardtechniques, such as solvent extraction, chromatography, crystallization,distillation and the like. Often, the product will be isolated as thehydrochloride or hydrobromide salt, and this material may be carriedonto the next step with or without purification.

Yet another method for the preparation of heterocyclic compounds ofFormula I is depicted in Scheme 7. In Scheme 7 W may be O or S, G ishalogen or a similar leaving group, L and B are as defined previously.The reaction conditions and purification procedures are as described forScheme 6.

In another embodiment of the present invention, depicted in Scheme 8, analkynyl-substituted heterocycle precursor (prepared using syntheticchemistry techniques well known in the art) is reacted with a species B,bearing a reactive functional group D. In Scheme 8, (R)_(q), W, X, Y, Zand B are as defined above and D and E are functional groups which arecapable of undergoing a transition metal-catalyzed cross-couplingreaction. For example, D is a group such as hydrogen, halogen, acyloxy,fluorosulfonate, trifluoromethanesulfonate, alkyl- or arylsulfonate,alkyl- or arylsulfinate, alkyl- or arylsulfide, phosphate, phosphinateand the like, and E is hydrogen or a metallic or metalloid species suchas Li, MgHal, SnR₃, B(OR)₂, SiR₃, GeR₃, and the like. The coupling maybe promoted by a homogeneous catalyst such as PdCl₂(PPh₃)₂, or by aheterogeneous catalyst such as Pd on carbon in a suitable solvent (e.g.THF, DME, MeCN, DMF etc.). Typically a co-catalyst such as copper (I)iodide and the like and a base (e.g. NEt₃, K₂CO₃ etc.) will also bepresent in the reaction mixture. The coupling reaction is typicallyallowed to proceed by allowing the reaction temperature to warm slowlyfrom about 0° C. up to ambient temperature over a period of severalhours. The reaction mixture is then maintained at ambient temperature,or heated to a temperature anywhere between 30° C. to 150° C. Thereaction mixture is then maintained at a suitable temperature for a timein the range of about 4 up to 48 hours, with about 12 hours typicallybeing sufficient. The product from the reaction can be isolated andpurified employing standard techniques, such as solvent extraction,chromatography, crystallization, distillation and the like.

Another embodiment of the present invention is illustrated in Scheme 9.An alkenyl-substituted heterocycle precursor is reacted with an alkenederivative in a manner similar to the procedure described for Scheme 8.The product alkene derivative from Scheme 9 may be converted to analkyne derivative using the approach outlined previously in Scheme 3above.

In yet another embodiment of the present invention, depicted in Scheme10, an alkynyl-substituted heterocycle precursor is reacted with aspecies composed of a carbonyl group bearing substituents R′ andCHR″R′″. Thus in Scheme 10, R′, R″ and R′″ may be hydrogen or othersubstituents as described previously, or may optionally combine to forma ring (this portion of the molecule constitutes B in the finalcompound). E is hydrogen or a metallic or metalloid species such as Li,MgHal, SnR₃, B(OR)₂, SiR₃, GeR₃, and the like. Suitable catalysts forthis reaction include bases such as NaH, nBuLi, LDA, LiHMDS, H₂NR, HNR₂,NR₃, nBu₄NF, EtMgHal etc., R in Scheme 10 may be hydrogen, Ac and thelike. Typically the reaction is carried out in a suitable solvent suchas Et₂O, THF, DME, toluene and the like, and at an appropriatetemperature, usually between −100° C. and 25° C. The reaction is allowedto proceed for an appropriate length of time, usually from 15 minutes to24 hours. The intermediate bearing the —OR group may be isolated andpurified as described above, partially purified or carried on to thenext step without purification. Elimination of the —OR group to providethe alkene derivative may be accomplished using a variety of methodswell known to those skilled in the art. For example, the intermediatemay be contacted with POCl₃ in a solvent such as pyridine and stirred ata suitable temperature, typically between 0° C. and 150° C., for anappropriate amount of time, usually between 1 h and 48 h. The productfrom the reaction can be isolated and purified employing standardtechniques, such as solvent extraction, chromatography, crystallization,distillation and the like.

The following examples are intended to illustrate but not to limit theinvention in any manner, shape, or form, either explicitly orimplicitly. While they are typical of those that might be used, otherprocedures, methodologies, or techniques known to those skill in the artmay alternatively be used.

EXAMPLE 1 Synthesis of 2-(1-Cyclohexen-1-ylethynyl)-1,3-thiazole

Triphenylphosphine (570 mg, 2.0 mmol) was dissolved in tetrahydrofuran(THF) (20 mL), then argon was bubbled through the solution for severalminutes to deoxygenate it. Palladium(II) acetate (120 mg, 0.54 mmol) wasadded, and the reaction mixture was heated to 60° C. for 0.5 h, and thencooled to ambient temperature. CuI (308 mg, 1.6 mmol),2-bromo-1,3-thiazole (3.0 g, 18 mmol), 1-ethynylcyclohexane (2.4 g, 20mmol), potassium carbonate (6 g, 45 mmol) and water (1.0 mL, 58 mmol)were dissolved in 50 mL dimethyoxyether (DME) and argon was bubbledthrough the solution for several minutes to deoxygenate the mixture. Thecatalyst solution of triphenylphosphine and palladium (II) acetate inTHF was added to the reaction flask which was heated to 75° C. for 2 h.After 2 h, heating was discontinued and the reaction was allowed to coolto ambient temperature. After stirring for 16 h, gas chromatography/massspectrometry (GC/MS) analysis showed the reaction to be complete. Themixture was filtered through Celite.™, the filter pad was washedthoroughly with ethyl acetate, and the combined filtrates wereconcentrated in vacuo. The residue was dissolved in ethyl acetate (200mL) and washed with water (200 mL), brine (200 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by columnchromatography eluting with hexane then 97:3 hexane:ethyl acetate toafford 2-(1-cyclohexen-1-ylethynyl)-1,3-thiazole (2.56 g, 74% yield) asa brown oil. ¹H NMR (CDCl₃, 300 MHz) Δ7.79 (d, J=3.0 Hz, 1H), 7.31 (d,J=3.0 Hz, 1H), 6.37-6.35 (m, 1H), 2.23-2.14 (m, 4H), 1.71-1.57 (m, 4H).MS (ESI) 190.0 (M⁺+H).

EXAMPLE 2 Synthesis of 2-Methyl-4-(1,3-thiazol-2-yl)-3-butyn-2-ol

2-Bromo-1,3-thiazole (6.0 g, 37 mmol) and CuI (1.3 g, 7.3 mmol) werecombined in DME (150 mL) and argon gas was bubbled through thesuspension for several minutes to deoxygenate the mixture. Triethylamine(25 mL, 180 mmol) and PdCl₂(PPh₃)₂ (2.5 g, 3.7 mmol) were added and2-methyl-3-butyne-2-ol (4.6 g, 55 mmol) was added dropwise. Afterstirring at ambient temperature for 16 h, GC/MS showed the reaction wasnot complete. The reaction was heated to reflux for 2 h. The mixture wasfiltered through Celite.™, the filter pad was washed thoroughly withethyl acetate, and the combined filtrates were concentrated in vacuo.The residue was dissolved in ethyl acetate (600 mL), washed with water(600 mL), brine (600 mL), dried over Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by column chromatography eluting withhexane then 7:3 hexane:ethyl acetate to afford4-(2-thiazolyl)-2-methyl-3-butyn-2-ol contaminated with2,7-dimethyl-but-3,5-diyne-2,7-diol. (The dimer of2-methyl-3-butyne-2-ol) The product was crystallized from boiling hexaneto afford 2-methyl-4-(1,3-thiazol-2-yl)-3-butyn-2-ol (2.18 g, 36% yield)as off white crystals that were contaminated with a small amount of2,7-dimethyl-but-3,5-diyne-2,7-diol. M.p. 69-70° C. ¹H NMR (CDCl₃, 300MHz) Δ7.80 (d, J=3.0 Hz, 1H), 7.34 (d, J=3.0 Hz, 1H), 4.40 (s, 1H), 1.65(s, 6H). MS (ESI) 168.1 (M⁺+H).

EXAMPLE 3 Synthesis of 5-Chloro-3-pyridinyl trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (5.0 mL, 30 mmol) was dissolved inCH₂Cl₂ (100 mL), and cooled to 0° C. 5-Chloro-3-pyridinol (3.10 g, 23.9mmol), and triethylamine (6.5 mL, 47 mmol) were dissolved in CH₂Cl₂ (50mL), and the resulting solution was added to the coldtrifluoromethanesulfonic anhydride solution dropwise via cannula. Theresulting dark brownish-red solution was stirred at 0° C. for 5 minutes,and then the ice bath was removed and the reaction mixture was allowedto warm to ambient temperature. After stirring for 16 h at ambienttemperature the reaction was quenched by pouring into water and basifiedby addition of saturated aqueous sodium carbonate. The basic aqueousphase was extracted with CH₂Cl₂ (2.times.50 mL), the combined organicsdried over Na₂SO₄, filtered and concentrated in vacuo. The resultingblack viscous oil was filtered through a plug of silica gel andfractions were collected while eluting with 1:1 hexane:ethyl acetate.Fractions containing the desired product were combined, concentrated invacuo, and further purified by column chromatography eluting with 15:1then 10:1 hexane:ethyl acetate to afford 5-chloro-3-pyridinyltrifluoromethanesulfonate (3.68 g, 59% yield) as a golden liquid. ¹H NMR(CDCl₃, 300 MHz) Δ8.65 (d, J=2 Hz, 1H), 8.52 (d, J=2 Hz, 1H), 7.70 (t,J=3 Hz, 1H). MS (ESI) 261 (M⁺, ³⁵Cl), 263 (M⁺, ³⁷Cl).

EXAMPLE 4 Synthesis of 3-Chloro-5-[(trimethylsilyl)ethynyl]pyridine

5-Chloro-3-pyridinyl trifluoromethanesulfonate (4.0 g, 15 mmol) and CuI(580 mg, 3.0 mmol) were combined in DME (100 mL) and argon gas wasbubbled through the suspension for several minutes to deoxygenate themixture. Triethylamine (10.6 mL, 76.5 mmol), and PdCl₂(PPh₃).su-b.2 (1.1g, 1.5 mmol) were added, then trimethylsilyl-acetylene (3.3 ml, 23 mmol)was added dropwise. The reaction mixture was stirred at ambienttemperature for 1 h at which time GC/MS analysis indicated that thereaction was complete. The mixture was filtered through Celite.™, andthe filter pad was washed thoroughly with ethyl acetate. The combinedfiltrates were concentrated in vacuo and the residue was dissolved inethyl acetate (300 mL), washed with water (300 mL), brine (300 mL),dried over Na₂SO₄ filtered, and concentrated in vacuo. The residue waspurified by column chromatography eluting with hexane then 99:1hexane:ethyl acetate to afford3-chloro-5-[(trimethylsilyl)ethynyl]pyridi-ne (2.8 g, 87% yield) as abrown solid. ¹H NMR (CDCl₃, 300 MHz) Δ8.51 (s, 1H), 8.44 (s, 1H), 7.70(s, 1H), 0.22 (s, 9H). MS (EI ionization) 209 (M⁺).

EXAMPLE 5 Synthesis of 3-Chloro-5-ethynylpyridine

3-Chloro-5-[(trimethylsilyl)ethynyl]pyridine (1.4 g, 6.7 mmol) wasdissolved in methanol (15 ml) and cooled to 0° C., to the resultingsolution was added potassium carbonate (93 mg, 0.67 mmol). The ice bathwas removed and the reaction mixture was stirred at ambient temperaturefor 0.5 h at which time thin layer chromatography (TLC) and GC/MSanalysis indicated that the reaction was complete. The solvent wasremoved in vacuo and the residue was dissolved in diethyl ether (50 mL),washed with water (100 mL), brine (100 mL), dried over Na₂SO₄, filtered,and concentrated in vacuo to afford 3-chloro-5-ethynylpyridine (822 mg,90% yield) which was pure by GC/MS analysis. MS (EI ionization) 137(³⁵Cl M⁺), 139 (³⁷Cl M⁺). This material was carried on to the next stepwithout further purification.

EXAMPLE 6 Synthesis of 3-Chloro-5-(1,3-thiazol-2-ylethynyl)pyridine

2-Bromo-1,3-thiazole (980 mg, 6.0 mmol) and CuI (230 mg, 1.2 mmol) werecombined in DME (15 mL) and argon gas was bubbled through the suspensionfor several minutes to deoxygenate the mixture. Triethylamine (4.2 mL,30 mmol) and PdCl₂(PPh₃)₂ (420 mg, 0.60 mmol) were added, then3-chloro-5-ethynylpyridine (820 mg, 19 mmol) was added dropwise. Afterstirring at ambient temperature for 16 h, GC/MS analysis showed startingmaterial remaining. The reaction mixture was heated at reflux for 2 h.The mixture was filtered through Celite.™, the filter pad was washedthoroughly with ethyl acetate, and the combined filtrates wereconcentrated in vacuo. The residue was dissolved in ethyl acetate (100mL), and washed with water (100 mL), brine (100 mL), dried over Na₂SO₄filtered and concentrated in vacuo. The residue was purified by columnchromatography eluting with hexane then 9:1 hexane:ethyl acetate toafford 3-chloro-5-(1,3-thiazol-2-ylethynyl)pyridi-ne which containedsome dimer. This material was crystallized from hot ethyl acetate toafford 3-chloro-5-(1,3-thiazol-2-ylethynyl)pyridine (300 mg 23% yield)as light orange crystals M.p. 124-125° C. ¹H NMR (CDCl₃, 300 MHz) Δ8.70(d, J=1.5 Hz, 1H), 8.59 (d, J=3.0Hz, 1H), 7.93 (d, J=3.0 Hz, 1H), 7.88(t, J=2.0 Hz, 1H), 7.48 (d, J=3.0 Hz, 2H). MS (ESI) 221.1 (M⁺+H).

EXAMPLE 7 Synthesis of 2-(Cyclohexylethyl)-1,3-thiazole

2-Bromo-1,3-thiazole (3.1 g, 19 mmol) and CuI (290 mg, 1.5 mmol) werecombined in DME (30 mL) and argon gas was bubbled through the suspensionfor several minutes to deoxygenate the mixture. Triethylamine (13 mL, 95mmol) and PdCl₂(PPh₃)₂ (530 mg, 0.76 mmol) were added andcyclohexylethyne (2.0 g, 19 mmol) was added dropwise. The reactionmixture was stirred at ambient temperature for 16 h at which time GC/MSanalysis indicated that the reaction was complete. The mixture wasfiltered through Celite.™, and the filter pad was washed thoroughly withethyl acetate. The combined filtrates were concentrated in vacuo and theresidue was dissolved in ethyl acetate (300 mL), washed with water (300mL), brine (300 mL), dried over Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by column chromatography eluting withhexane then 99:1 hexane:ethyl acetate to afford2-(cyclohexylethynyl)-1,3-thiazole (1.6 g, 44% yield) as a yellow oil.¹H NMR (CDCl₃, 300 MHz) Δ7.76 (d, J=9.0 Hz, 1H), 7.28 (d, J=3.0 Hz, 1H),2.68-2.59 (m, 1H), 1.91-1.28 (m, 10H). MS (ESI) 191.7 (M⁺).

EXAMPLE 8 2-(1-Pentynyl)-1,3-thiazole

2-Bromo-1,3-thiazole (2.0 g, 12 mmol) and CuI (183 mg, 0.96 mmol) werecombined in DME (30 mL) and argon gas was bubbled through the suspensionfor several minutes to deoxygenate the mixture. Triethylamine (8 mL, 60mmol) and PdCl₂(PPh₃)₂ (337 mg, 0.48 mmol) were added and 1-pentyne (979mg, 14.4 mmol) was added dropwise. The reaction mixture was stirred atambient temperature for 6 h at which time GC/MS analysis indicated thatthe reaction was not complete. Additional 1-pentyne (3.0 mL, 29 mmol)was added and the reaction was heated to 35° C. under a condenser. Afterheating for 16 h, GC/MS analysis indicated that the reaction wascomplete. The mixture was filtered through Celite.™, and the filter padwas washed thoroughly with ethyl acetate. The combined filtrates wereconcentrated in vacuo and the residue was dissolved in ethyl acetate(300 mL), washed with water (300 mL), brine (300 mL), dried over Na₂SO₄filtered, and concentrated in vacuo. The residue was purified by columnchromatography eluting with hexane, 99:1, then 97:3 hexane:ethyl acetateto 2-(1-pentynyl)-1,3-thiazole (820 mg, 44% yield) as a yellow oil. ¹HNMR (CDCl₃, 300 MHz) Δ7.76 (d, J=3.0 Hz, 1H), 7.28 (d, J=3.0 Hz, 1H),2.47-2.42 (m, 2H), 1.68-1.60 (m, 2H), 1.08-0.99 (m, 3H). MS (ESI) 151.6(M⁺).

EXAMPLE 9 2-(3-Cyclohexyl-1-propynyl)-1,3-thiazole

2-Bromo-1,3-thiazole (2.0 g, 12 mmol) and CuI (185 mg, 0.97 mmol) werecombined in DME (30 mL) and argon gas was bubbled through the suspensionfor several minutes to deoxygenate the mixture. Triethylamine (8.5 mL,61 mmol) and PdCl₂(PPh₃)₂ (340 mg, 0.49 mmol) were added and3-cyclohexyl-1-propyne (2.9 g, 24 mmol) was added dropwise. The reactionwas stirred at ambient temperature for 16 h at which time GC/MS analysisindicated that the reaction was complete. The mixture was filteredthrough Celite.™, and the filter pad was washed thoroughly with ethylacetate. The combined filtrates were concentrated in vacuo. The residuewas dissolved in ethyl acetate (300 mL), washed with water (300 mL),brine (300 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo.The residue was purified by column chromatography eluting with hexane,then 98:2 hexane:ethyl acetate to afford2-(3-cyclohexyl-1-propynyl)-1,3-thiazole (1.14 g, 46% yield) as a yellowoil. ¹H NMR (CDCl₃, 300 MHz) Δ7.76 (d, J=3.0 Hz, 1H), 7.27 (d, J=3.0 Hz,1H), 2.35 (d, J=6 Hz, 2H), 1.89-1.61 (m, 5H), 1.3-1.03 (m, 6H). MS (ESI)205.9 (M^(+H).)

EXAMPLE 10 Synthesis of2-(1-Cyclohexen-1-ylethynyl)-5-nitro-1,3-thiazole

2-Bromo-5-nitro-1,3-thiazole (2.5 g, 12 mmol) and CuI (460 mg, 2.5 mmol)were combined in DME (30 mL) and argon gas was bubbled through thesuspension for several minutes to deoxygenate the mixture. Triethylamine(8.4 mL, 60 mmol) and PdCl₂(PPh₃)₂ (840 mg, 1.2 mmol) were added and1-ethynycyclohezene (1.5 g, 14.4 mmol) was added dropwise. The reactionwas heated under reflux for 16 h at which time GC/MS analysis indicatedthat the reaction was complete. The mixture was filtered throughCelite.™, and the filter pad was washed thoroughly with ethyl acetate.The combined filtrates were concentrated in vacuo and the residue wasdissolved in ethyl acetate (300 mL), washed with water (300 mL), brine(300 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography eluting with hexane, 99:1then 98.5:1.5 hexane:ethyl acetate to afford2-(1-cyclohexen-1-ylethynyl)-5-nitro-1,3-thiazole (1.4 g, 51.8% yield)as a yellow powder. M.p. 85-86° C. ¹H NMR (CDCl₃, 300 MHz) Δ8.5 (s, 1H),6.52 (br s, 1H), 2.24 (br s, 4H), 1.63 (br s, 4H). MS (ESI) 235.1(M⁺+H).

EXAMPLE 11 Synthesis of 2-(3,3-Dimethyl-1-butynyl-1,3-thiazole

Triphenylphosphine (380 mg, 1.5 mmol) was dissolved in TBF (20 mL), thenargon was bubbled through the solution for several minutes todeoxygenate it. Palladium(II) acetate (82 mg, 0.37 mmol) was added, andthe reaction mixture was heated to 60° C. for 0.5 h, and then cooled toambient temperature. CuI (210 mg, 1.1 mmol), 2-bromo-1,3-thiazole (1.6g, 9.8 mmol), potassium carbonate (4.2 g, 31 mmol) and water (0.70 mL,39 mmol) were dissolved in DME (30 mL) and argon was bubbled through themixture for several minutes to deoxygenate the mixture.3,3-dimethyl-1-butyne (1.0 g, 12.2 mmol) was then added to mixture. Thecatalyst solution of triphenylphosphine and palladium (II) acetate inTHF was added to the reaction flask which was heated to 30° C. for 2 h.After this time heating was discontinued and the mixture was allowed tostir at ambient temperature. After stirring for 16 h, GC/MS analysisshowed the reaction to be complete. The mixture was filtered throughCelite.™, the filter pad was washed thoroughly with ethyl acetate, andthe combined filtrates were concentrated in vacuo. The residue wasdissolved in ethyl acetate (200 mL), washed with water (200 mL), brine(200 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography eluting with hexane, then99:1 hexane:ethyl acetate to afford2-(3,3-dimethyl-1-butynyl)-1,3-thiazole (0.45 g, 28% yield) as a yellowoil. ¹H NMR (CDCl₃, 300 MHz) Δ7.74 (d, J=3.0 Hz, 1H), 7.28 (d, J=3.0 Hz,1H), 1.33 (s, 9H). MS (ESI) 166.1 (M⁺+H).

EXAMPLE 12 Synthesis of 1-(1,3-Thiazol-2-ylethynyl)cyclopentanol

2-Bromo-1,3-thiazole (3.1 g, 19 mmol) and CuI (360 mg, 1.9 mmol) werecombined in DME (30 mL) and argon gas was bubbled through the suspensionfor several minutes to deoxygenate the mixture. Triethylamine (13 mL, 94mmol) and PdCl₂(PPh₃)₂ (660 mg, 0.94 mmol) were added and1-ethynycyclopentanol (2.5 g, 23 mmol) was added dropwise. The reactionwas heated at 50° C. for 16 h at which time GC/MS analysis indicatedthat the reaction was complete. The mixture was filtered throughCelite.™, and the filter pad was washed thoroughly with ethyl acetate.The combined filtrates were concentrated in vacuo and the residue wasdissolved in ethyl acetate (300 mL), washed with water (300 mL), brine(300 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography eluting with hexane, 6:1then 3:1 hexane:ethyl acetate to afford1-(1,3-thiazol-2-ylethynyl)cyclopentanol (2.3 g, 52% yield) as a yellowpowder. ¹H NMR (CDCl₃, 300 MHz) Δ7.80 (d, J=3 Hz, 1H), 7.65 (d, J=3 Hz,1H), 2.04-1.73 (m, 10.8H). MS (EI ionization) 193 (M⁺).

EXAMPLE 13 Synthesis of 2-(1-Cyclopenten-1-ylethynyl)-1,3-thiazole

1-(1,3-Thiazol-2-ylethynyl)cyclopentanol was dissolved in pyridine (20ml) and phosphorus oxychloride (1.2 g, 6.2 mmol) was added dropwiseunder argon. The reaction was stirred at ambient temperature for 1 h atwhich time a precipitate had appeared. At this time GC/MS analysisindicated that the reaction was complete and the pyridine was removed invacuo. The residue was dissolved in ethyl acetate (200 mL) and washedwith water (200 mL), brine (200 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by column chromatographyeluting with hexane then 99:1 hexane:ethyl acetate to2-(1-cyclopenten-1-ylethynyl)-1,3-thiazole (0.25 g, 24% yield) as alight brown solid. M.p. 70.5-72° C., ¹H NMR (CDCl₃, 300 MHz) Δ7.80 (d,J=3.0 Hz, 1H), 7.34 (d, J=3.0 Hz, 1H), 6.31-6.30 (m, 1H), 2.60-2.45 (m,4H), 2.00-1.90 (m, 2H). MS (ESI) 176.1 (M⁺+H).

EXAMPLE 14 Synthesis of Methyl 3-(1,3-thiazol-2-yl)-2-propynyl ether

2-Bromo-1,3-thiazole (2.0 g, 12 mmol) and CuI (456 mg, 2.4 mmol) werecombined in DME (30 mL) and argon gas was bubbled through the suspensionfor several minutes to deoxygenate the mixture. Triethylamine (8.6 mL,60 mmol) and PdCl₂(PPh₃)₂ (842 mg, 1.2 mmol) were added and methylpropargyl ether (1.00 g, 14.4 mmol) was added dropwise. The reaction wasstirred at 55° C. under a condenser. After stirring at 55° C. for 16 h,GC/MS analysis indicated that the reaction was complete. The mixture wasfiltered through Celite.™, and the filter pad was washed thoroughly withethyl acetate. The combined filtrates were concentrated in vacuo and theresidue was dissolved in ethyl acetate (300 mL), washed with water (300mL), brine (300 mL), dried over Na₂SO₄ filtered, and concentrated invacuo. The residue was purified by column chromatography eluting withhexane, 99:1, 97:3, then 96:4 hexane:ethyl acetate to afford methyl3-(1,3-thiazol-2-yl)-2-propynyl ether (250 mg, 13% yield) as a yellowoil. ¹H NMR (CDCl₃, 300 MHz) Δ7.78 (d, J=3.0 Hz, 1H), 7.37 (d, J=3.0 Hz,1H), 4.37 (s, 2H), 3.47 (s, 3H). MS (ESI) 154.1 (M⁺+H).

EXAMPLE 15 Synthesis of 2-Methyl-4-(3-pyridinyl)-3-butyn-2-ol

3-Bromopyridine (3.0 mL, 31 mmol), triethylamine (22 mL, 160 mmol), CuI(1.2 g, 6.2 mmol), and PdCl₂(PPh₃)₂ (1.1 g, 1.5 mmol) were combined inDME (92 mL) and cooled to 0° C. 2-Methyl-3-butyne-2-ol (9.0 mL, 93 mmol)was then added and the reaction was allowed to slowly warm to ambienttemperature. The mixture was then heated to 55-60° C. for 16 h. Themixture was filtered through Celite.™, and the pad was washed thoroughlywith ethyl acetate. The combined filtrates were washed with brine(3.times.100 mL), dried over MgSO₄, and filtered. The solution wasconcentrated in vacuo, and the residue was purified by columnchromatography eluting with 90:10 hexane:ethyl acetate then ethylacetate to afford 2-methyl-4-(3-pyridinyl-)-3-butyn-2-ol (2.0 g, 40%yield) as a brown oil ¹H NMR (CDCl₃, 300 MHz) Δ8.76 (br s, 1H), 8.52 (brs, 1H), 7.74-7.70 (m, 1H), 4.08 (br s, 1H), 1.63 (s, 3H). MS (EIionization) 161 (M⁺).

EXAMPLE 16 Synthesis of 3-Ethynylpyridine

2-Methyl-4-(3-pyridinyl)-3-butyn-2-ol (611 mg, 3.79 mmol) was dissolvedin toluene (12 mL) at ambient temperature. A small amount (spatula tip)of NaH (60% dispersion in mineral oil) was added, and the reaction washeated to reflux. After 15 minutes the reaction was cooled to ambienttemperature, and quenched by the addition of 1M aqueous HCl (30 mL).Crude product from a previous preparation (.about.200 mg) was added tothe workup mixture. The acidic aqueous was extracted with ethyl acetate(2.times.20 mL), basified by the addition of saturated aqueous NaHCO₃,and extracted with CH₂Cl₂. The CH₂Cl₂ extracts were dried over MgSO₄,filtered, and concentrated in vacuo to afford crude 3-ethynylpyridine(1.5 g, >100%) as a brown liquid. ¹H NMR (CDCl₃, 300 MHz) Δ8.73 (br s,1H), 8.58 (br s, 1H), 7.80-7.76 (m, 1H), 7.29-7.16 (m, 1H), 3.28 (s,1H). A portion of this material was carried on to the next step withoutfurther purification.

EXAMPLE 17 Synthesis of 3-(1,3-Thiazol-2-ylethynyl)pyridine

2-Bromo-1,3-thiazole (0.15 mL, 1.6 mmol), CuI (98 mg, o.51 mmol),PdCl₂(PPh₃)₂ (120 mg, 0.17 mmol) and triethylamine (2.8 mL, 20 mmol)were combined in DMF (6.8 mL) and cooled in an ice bath.3-Ethynylpyridine (520 mg, 5.04 mmol) was then added to the mixture as asolution in DMF (3.0 ML). The ice bath was removed and the reaction wasallowed to stir at ambient temperature for 16 h. The reaction mixturewas filtered through a pad of Celite.™, and the pad was washedthoroughly with ethyl acetate. The filtrate was washed with brine(3.times.20 mL). A partial emulsion was observed. The mixture wasconcentrated in vacuo and the residue was taken up in CH₂Cl₂, washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by column chromatography on silica geleluting with 80:20 followed by 30:20 hexane:ethyl acetate to afford3-(1,3-thiazol-2-ylethynyl)pyridine (160 mg) as a mixture with anotherproduct exhibiting a mass of 204 in the GC/MS, assigned as pyridylalkynedimer. A portion of the mixture (100 mg) was further purified bypreparative reverse phase HPLC eluting with a gradient of 80:20 to 0:100water: acetonitrile over twenty minutes. The fractions containing thedesired product were collected (detection by uv at 210 nm) to afford3-(1,3-thiazol-2-ylethynyl)pyridine as a white waxy solid (15 mg). ¹HNMR (CDCl₃, 300 MHz) Δ9.3-8.5 (br s, 2H), 7.92-7.90 (m, 2H), 7.50-7.30(m, 2H). MS (ESI) 187.0 (M⁺+H).

EXAMPLE 18 Synthesis of3,3,5,5-Tetramethyl-1-(2-pyridinylethynyl)cyclohexanol

To a solution of 2-ethynylpyridine (1.0 g, 10 mmol) in TBF at −78° C.was added a 1.0 M solution of ethyl magnesium bromide in THF (10 mL, 10mmol). After stirring at reduced temperature for 30 minutes a solutionof 3,3,5,5-tetramethyl-cyclohexanone (1.5 g, 10 mmol) in THF was addedrapidly. The mixture was allowed to warm to ambient temperature over 16hours, then partitioned between water and ethyl acetate. The organiclayer was dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresultant product was purified by flash column chromatography on silicagel eluting with 1:1 hexane:ethyl acetate to afford3,3,5,5-tetramethyl-1-(2-pyridinylethynyl)cyclohexanol (250 mg, 10%yield) as a white solid. M.p. 126-127° C. ¹H NMR (DMSO-d₆, 300 MHz)Δ8.57 (m, 1H), 7.64 (m, 1H), 7.39 (d, J=5 Hz, 1H), 7.22 (m, 1H), 1.91(d, J=9 Hz, 2H), 1.71 (d, J=9 Hz, 2H), 1.26 (s, 2H), 1.14 (s, 6H), 1.09(s, 6H).

EXAMPLE 19 Synthesis of2-[(3,3,5,5-Tetramethyl-1-cyclohexen-1-yl)ethynyl]pyridine

3,3,5,5-Tetramethyl-1-(2-pyridinylethynyl)cyclohexanol (200 mg, 0.78mmol) was dissolved in pyridine. POCl₃ (153 mg, 1.0 mmol) was added, andthe mixture was heated to reflux for 6 h. After cooling, the POCl₃ andpyridine were removed in vacuo. The residue was purified by flash columnchromatography on silica gel eluting with 2:1 hexane:ethyl acetate toafford 2-[(3,3,5,5-tetramethyl-1-cyclohexen-1-yl)-ethynyl]pyridine (148mg, 80% yield) as a light tan solid. M.p. 55-56° C. ¹H NMR (CDCl₃, 300MHz) Δ8.56 (m, 1H), 7.62 (m, 1H), 7.40 (d, J=7 Hz, 1H), 7.18 (m 1H),6.09 (s, 1H), 2.00 (s, 2H), 1.35 (s, 2H), 1.05 (s, 6H), 0.99 (s, 6H).

EXAMPLE 20 Synthesis of 2-[(5-Methyl-1-cyclohexen-1-yl)ethvnyl]pyridineand 2-[(3-methyl-1-cyclohexen-yl)ethynyl]pyridine (1:1)

Using the procedures for Examples 18 and 19 but with the appropriatestarting materials, 2-[(5-methyl-1-cyclohexen-1-yl)ethynyl]py-ridine and2-[(3-methyl-1-cyclohexen-1-yl) ethynyl]pyridine were obtained as amixture of racemic regioisomers. ¹H NMR (CDCl₃, 300 MHz) Δ8.56 (m, 1H),7.62 (m, 1H), 7.40 (m, 1H), 7.19 (m, 1H), 6.32 (s, 0.5H), 6.20 (s, 0.5H), 2.25 (m, 3H), 1.73 (m, 3H), (m, 1H), 1.01 (m, 3H). MS (EIionization) Two peaks: 197 (M⁺).

EXAMPLE 21 General Procedure for 2-pyridylenynes

To a cooled a solution of 2-ethynylpyridine in THE to −78° C. was addedn-BuLi (1.6 M in hexane, 1 equiv). After 20 minutes stirring at reducedtemperature this material was mixed with a solution of the appropriateketone (1 equiv) in THF. The solution was allowed to warm slowly toambient temperature. The reaction mixture was then quenched andpartitioned between water and ethyl acetate. The organic layer was driedover Na₂SO₄, and concentrated in vacuo. The resultant product waspurified by flash column chromatography on silica gel eluting with 1:1hexane:ethyl acetate. The resulting product was dissolved in pyridine ora mixture of pyridine and methylene chloride (1:1). POCl₃ (1.2 equiv)was added and the solution refluxed for 4 to 8 hours. The resultantmixture was partitioned between 1M K₂CO₃ and ethyl acetate. The organiclayer was dried over Na₂SO₄, and concentrated in vacuo. The resultantproduct was purified by flash column chromatography on silica geleluting with 2:1 hexane:ethyl acetate.

Using this general procedure the following example compounds (seeExamples 22-33) were obtained.

EXAMPLE 22 Synthesis of 2-[(4-Methyl-1-cyclopenten-1-yl)ethynyl]pyridineand 2-[(3-Methyl-1-cyclopenten-1-yl)ethynyl]pyridine (1:1)

Reactants: 2-ethynylpyridine (620 mg, 6.0 mmol), 3-methylcyclopentanone(0.64 mL, 6.0 mmol); yields2-[(4-methyl-1-cyclopenten-1-yl)ethynyl]pyridine and2-[(3-methyl-1-cyclopenten-1-yl)ethynyl]pyridine (1:1) as a transparentoil (200 mg, 18% overall yield), as mixture of regio- and stereoisomers.¹H NMR (CDCl₃, 300 MHz) Δ8.56 (m, 1H), 7.64 (m, 1H), 7.44 (m, 1H), 7.20(m, 1H), 6.19 (m, 0.5H), 6.18 (m, 0.5H), 2.90 (m, 0.5H), 2.70 (m, 2.5H),2.21 (m, 2H), 1.48 (m, 0.5H), 1.08 (app d, J=7.5 Hz, 3H). Two peaks: 182(M⁺), 167 (M⁺−Me).

EXAMPLE 23 Synthesis of 2-(Bicyclo[2.2.1]hept-2-en-2-ylethynyl)pyridine

Reactants: 2-ethynylpyridine (1.0 g, 10.0 mmol), norcamphor (1.1 g, 10.0mmol); yields 2-(bicyclo[2.2.1]hept-2-en-2-ylethynyl)pyridine as a blackoil (215 mg, 11% over two steps). This material was mixed with fumaricacid (128 mg, 1.11 mmol), dissolved in MeOH and the resulting solutionwas concentrated in vacuo to afford a dark brown solid. This wastriturated with a mixture of ethyl acetate:ethanol (1:1) and theresultant solids were partitioned between aqueous K₂CO₃ and ethylacetate. The organics were dried over Na₂SO₄, and concentrated in vacuo.The residue was purified by flash column chromatography on silica geleluting with 2:1 hexane:ethyl acetate to afford2-(bicyclo[2.2.1]hept-2-en-2-ylethynyl)pyridine (30 mg, 1.5% overallyield) as a translucent brown oil. ¹H NMR (DMSO-d₆, 300 MHz) Δ8.58 (d,J=5 Hz, 1H), 7.64 (m, 1H), 7.40 (m, 1H), 7.19 (m, 1H), 6.48 (d, J=4 Hz,1H), 3.07 (s, 1H), 2.97 (s, 1H), 1.76 (m, 2H), 1.51 (m, 1H), 1.23 (m,1H), 1.11 (m, 1H). MS (EI ionization) 195 (M⁺).

EXAMPLE 24 Synthesis of2-[(2,6-Dimethyl-1-cyclohexen-1-yl)ethenyl]pyridine

Reactants: 2-ethynylpyridine (5.0 mmol, 515 mg),2,6-dimethylcyclopentanone (6.0 mmol, 0.82 mL); yields2-[(2,6-dimethyl-1-cyclohexen-1-yl)ethynyl]pyridine as a transparent oil(200 mg, 19% overall yield). 1H NMR (CDCl₃, 300 MHz) 67 8.56 (m, 1H),7.60 (m, 1H), 7.42 (m, 1H), 7.19 (m, 1H), 2.40 (m, 1H), 2.10 (m, 2H),2.01 (s, 3H), 1.76 (m, 2H), 1.56 (m, 1H), 1.34 (m, 1H) (app d, J=7 Hz,3H). MS (EI ionization) 211 (M⁺).

EXAMPLE 25 Synthesis of 2-(1-Cyclohepten-1-ylethynyl)pyridine

Reactants: 2-ethynylpyridine (5.0 mmol, 515 mg), cycloheptanone (6.0mmol, 0.71 mL); yields 2-(1-cyclohepten-1-ylethynyl)pyridine as atransparent oil (200 mg, 18% overall yield). ¹H NMR (CDCl₃, 300 MHz)Δ8.54 (m, 1H), 7.59 (m, 1H), 7.40 (m, 1H), 7.16 (m, 1H), 6.52 (t, J=7Hz, 1H), 2.47 (m, 2H), 2.26 (m, 2H), 1.77 (s, 2H), 1.61 (m, 2H), 1.56(m, 2H). MS (EI ionization) 197 (M⁺).

EXAMPLE 26 Synthesis of 2-(1-Cycloocten-1-ylethynyl)pyridine

Reactants: 2-ethynylpyridine (515 mg, 5.0 mmol), cyclooctanone (756 mg,6.0 mmol); yields 2-(1-cycloocten-1-ylethynyl)pyridine as a transparentoil (250 mg, 24% overall yield). ¹H NMR (CDCl₃, 300 MHz) Δ8.57 (m, 1H),7.62 (m, 1H), 7.40 (m, 1H), 7.18 (m, 1H), 6.33 (t, J=7 Hz, 1H), 2.41 (m,2H), 2.23 (m, 2H), 1.66 (s, 2H), 1.52 (br m, 6H). MS (EI ionization) 211(M⁺).

EXAMPLE 27 Synthesis of 2-[(4-Methyl-1-cyclohexen-1-yl)ethynyl]pyridine

Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), 4-methylcyclohexanone(6.0 mmol, 672 mg); yields2-[(4-methyl-1-cyclohexe-n-1-yl)ethynyl]pyridine as a transparent oil(250 mg, 21% overall yield). ¹H NMR (CDCl₃, 300 MHz) Δ8.57 (m, 1H), 7.59(m, 1H), 7.39 (m, 1H), 7.20 (m, 1H), 6.30 (m, 1H), 2.22 (m, 3H), 1.25(m, 1H), 0.99 (m, 3H). MS (EI ionization) 197 (M⁺).

EXAMPLE 28 Synthesis of 2-(3,6-Dihydro-2H-thiopyran-4-ylethynyl)pyridine

Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg),tetrabydrothiopyran-4-one (6.0 mmol, 696 mg); yields2-(3,6-dihydro-2H-thiopyran-4-ylethynyl)pyridine as a transparent oil(150 mg, 12% overall yield). ¹H NMR (CDCl₃, 300 MHz) Δ8.57 (m, 1H), 7.61(m, 1H), 7.40 (m, 1H), 7.21 (m, 1H), 6.46 (m, 1H), 3.27 (m, 2H), 2.57(m, 2H). MS (EI ionization) 201 (M⁺).

EXAMPLE 29 Synthesis of 2-(3,6-Dihydro-2H-pyran-4-ylethynyl)pyridine

Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg),tetrahydro-4H-pyran-4-one (6.0 mmol, 600 mg); yields2-(3,6-dihydro-2H-pyran-4-ylethynyl)pyridine as a transparent oil (200mg, 18% overall yield). ¹H NMR (CDCl₃, 300 MHz) Δ8.57 (m, 1H), 7.63 (m,1H), 7.44 (m, 1H), 7.21 (m, 1H), 6.29 (m, 1H), 4.25 (m, 2H) 3.81 (m,2H), 2.36 (m, 2H). MS (EI ionization) 185 (M⁺).

EXAMPLE 30 Synthesis of2-{[(1R)-1,7,7-Trimethylbicyclo[2.2.1]hept-2-en-2-yl]ethynyl}-pyridine

Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), (1R)-(+)-camphor (6.0mmol, 912 mg); yields2-{[(1R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-e-n-2-yl]ethynyl }pyridineas a transparent yellow oil (125 mg, 9% overall yield). ¹H NMR (CDCl₃,300 MHz) Δ8.57 (m, 1H), 7.64 (m, 1H), 7.43 (m, 1H), 7.17 (m, 1H), 6.49(d, J=3 Hz, 1H), 2.41 (t, J=3 Hz, 1H), 1.92 (br m, 1H), 1.65 (m, 1H),1.18 (m, 1H), 1.17 (s, 3H), 1.09 (br m, 1H), 0.84 (s, 3H), 0.82 (s, 3H).MS (EI ionization) 237 (M⁺).

EXAMPLE 31 Synthesis of2-[(3,5-Dimethyl-1-cyclohexen-1-yl)ethynyl]pyridine

Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg),3,5-dimethylcyclohexanone (6.0 mmol, 0.85 mL); yields2-[(3,5-dimethyl-1-cyclohexen-1-yl)ethynyl]pyridine as a transparentyellow oil (500 mg, 39% overall yield) as a mixture of diastereomers. ¹HNMR (CDCl₃, 300 MHz) 67 8.57 (m, 1H), 7.62 (m, 1H), 7.40 (m, 1H), 7.19(m, 1H), 6.15 (br s, 1H), 2.29 (m, 2H), 1.80 (br m, (2H), 1.00 (m, 6H),0.88 (br m, 2H). MS (EI ionization) 211 (M⁺).

EXAMPLE 32 Synthesis of2-{[(5R)-5-Methyl-1-cyclohexen-1-yl]ethynyl}pyridine compound with2-{[(3R)-3-methyl-1-cyclohexen-1-yl]ethynyl}pyridine (1:1)

Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg),(3R)-(+)-3-methylcyclohexanone (6.0 mmol, 0.73 mL); yields2-{[(5R)-5-methyl-1-cyclohexen-1-yl]ethynyl}pyridine and2-{[(3R)-3-methyl-1-cyclohexen-1-yl]ethynyl}pyridine (1:1) as atransparent yellow oil (440 mg, 37% overall yield) as a mixture ofregioisomers. 1H NMR (CDCl₃, 300 MHz) Δ8.56 (m, 1H), 7.62 (m, 1H), 7.40(m, 1H), 7.18 (m, 1H), 6.31 (m, 0.5H), 6.19 (m, 0.5H), 2.30 (m, 3H),1.85 (m, 2.5H), 1.22 (m, 1H), 0.98 (m, 3.5H). MS (EI ionization) 197(M⁺) two peaks resolved.

EXAMPLE 33 Synthesis of 2-[(3E)-3-Methyl-3-penten-1-vinyl]pyridine,2-(3-ethyl-3-buten-1-ynyl pyridine and2-[(3Z)-3-methyl-3-penten-1-]pyri-dine

Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), 2-butanone (6.0 mmol,0.54 mL); yields 2-[(3E)-3-methyl-3-penten-1-yny]pyridine,2-(3-ethyl-3-buten-1-ynyl)pyridine and 2-[(3Z)-3-penten-1-ynyl]-pyridineas a transparent oil (135 mg, 14% overall yield) as a mixture of E, Zand exo-methylene isomers. ¹H NMR (CDCl₃, 300 MHz) Δ8.59 (m, 1H), 7.65(m, 1H) 7.44 (m, 1H), 7.20 (m, 1H), 5.88 (m, 0.75H), 5.53 (s, 0.33H)5.40 (s, 0.33H), 2.29 (q, J=7 Hz, 0.65H), (m, 4.5H), 1.17 (t, J=7 Hz,1H). MS (EI ionization) 157 (M⁺) two peaks resolved.

EXAMPLE 34 Synthesis of 5-Ethyl-2-(phenylethynyl)pyrimnidinehydrochloride

2-Chloro-5-ethylpyrimdine (500 mg, 3.5 mmol), PdCl₂(PPh₃)₂ (250 mg, 0.35mmol), CuI (203 mg, 1.06 mmol), triethylamne (6.0 mL, 43 mmol), andn-Bu₄NI (3.85 g, 10.4 mmol) were combined in dimethylformamide (DMF) (30mL). The mixture was cooled in an ice bath and then phenylacetylene (1.5mL, 14 mmol) was added. The reaction mixture was then heated to 45-50°C. and after 1.5 h, additional phenylacetylene (1.5 mL, 14 mmol) wasadded. After an additional 17 h the reaction was diluted with ethylacetate, washed with brine (4.times.15 mL), dried over Na₂SO₄, filtered,and concentrated in vacuo. The resulting black oil was purified bycolumn chromatography eluting with hexane then 90:10 hexane:ethylacetate to afford 5-ethyl-2-(phenylethynyl)pyrimdine (770 mg, >100%) asa black oil. MS (EI ionization) 208 (M⁺). This material was carried onto the salt formation without further purification.

5-Ethyl-2-(phenylethynyl)pyrimdine (730 mg, 3.7 mmol) was dissolved inCH₂Cl₂ (3.0 mL) and treated with HCl in diethyl ether (4.1 mL of a 1Nsolution, 4.1 mmol). Upon addition of the HC₁solution a solidprecipitated from the solution. The mixture was diluted with diethylether (2 mL) and the supernatant decanted. The resultant solid was driedunder high vacuum at 50° C. to afford 5-ethyl-2-(phenylethynyl)pyrimdinehydrochloride (450 mg, 49% yield) as an orange solid. M.p. 101-104° C.¹H NMR (CD₃OD, 300 MHz) Δ8.75 (s, 2H), 7.58-7.55 (m, 2H), 7.41 (m, 3H),2.67 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H).

EXAMPLE 35 Synthesis of 4,6-Dimethoxy-2-(phenylethenyl)pyrimdinehydrochloride

2-Chloro-4,6-dimethoxypyrimdine (500 mg, 2.9 mmol), PdCl₂(PPh₃)₂ (200mg, 0.28 mmol CuI (160 mg, 0.84 mmol), triethylamne (4.8 mL, 34 mmol),and n-Bu₄NI (3.2 g, 8.7 mmol) were combined in DMF (24 mL). The mixturewas cooled in an ice bath and then phenylacetylene (1.25 mL, 11.4 mmol)was added. The reaction mixture was allowed to warm to ambienttemperature. After 2.5 h at ambient temperature the reaction mixture washeated to 45-50° C. After 2 h, additional phenylacetylene (1.0 mL, 9.1mmol) was added. After an additional 17 h stirring at 45-50° C., thereaction mixture was filtered through a pad of Celite.™, and the filterpad was washed thoroughly with ethyl acetate. The combined filtrateswere washed with brine (4.times.20 mL), dried over MgSO₄, filtered andconcentrated in vacuo. The resulting black oil was purified by columnchromatography eluting with hexane, 90:10, then 85:15 hexane:ethylacetate to afford product contaminated with an impurity. Careful columnchromatography of this impure material eluting with hexane then 90:10hexane:ethyl acetate afforded 4,6-dimethoxy-2-(phenylethynyl)pyrimdine(320 mg, 46% yield) as a yellow solid. This material was carried on tothe salt formation without further purification.

4,6-Dimethoxy-2-(phenylethynyl)pyrimdine (320 mg, 1.3 mmol) wasdissolved in CH₂Cl₂ (1.0 mL), and treated with HCl in diethyl ether (1.6mL of a 1.0M solution, 1.6 mmol). A yellow solid precipitatedimmediately. The mixture was diluted with ethyl acetate and allowed tostand in the freezer for 16 h. The cold supernatant was decanted and theremaining solids were triturated with ethyl acetate (1.5 mL), and thenhexane (3.times.2 mL). The remaining solid was dried in vacuo to afford4,6-dimethoxy-2-(phenylethynyl)pyrimdine hydrochloride (174 mg, 47%yield) as a yellow solid. M.p. 137-138. ¹H NMR (CD₃OD, 300 MHz)Δ7.65-7.62 (m, 2H), 7.46-7.42 (m, 3H), 6.16 (s, 1H), 3.97 (s, 6H).

EXAMPLE 36 Synthesis of2-[(E)-2-(3-Fluorophenol)ethenyl]-6-methylpyrazine

2,6-Dimethylpyrazine (5.0 g, 46 mmol) was dissolved in THF (200 mL) andcooled to 0° C. Potassium t-butoxide (46 mL of a 1.0M solution in THf,46 mmol) was added to afford a dark red solution. The solution wasallowed to warm to ambient temperature and stir for 1 hr. The solutionwas then cooled to 0° C., and 3-fluorobenzaldehyde (4.9 mL, 46 mmol) wasadded via syringe pump over 2 h. The reaction was then allowed to slowlywarm to ambient temperature. After stirring at ambient temperature for18 h, the reaction mixture was cooled to 0° C. and quenched by theaddition of concentrated aqueous HCl (10 mL). The resulting suspensionwas allowed to warm to ambient temperature for 15 minutes, then cooledto 0° C. and brought to pH=8 by addition of solid NaHCO₃. The layerswere separated, and the aqueous layer was extracted with ethyl acetate(3.times.200 mL). The combined organic layers were washed with brine(200 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Thecrude product was purified by column chromatography eluting with 90:10,85:15, then 80:20 hexane:ethyl acetate to afford2-[(E)-2-(3-fluorophenyl)ethenyl]-6-methylpyrazine (4.14 g, 42% yield)as a light yellow solid. M.p. 43-44° C. ¹H NMR (CDCl₃, 300 MHz) Δ8.44(s, 1H), 8.31 (s, 1H), 7.29 (d, J=16 Hz, 1H), 7.37-7.26 (m, 3H), 7.12(d, J=16 Hz, 1H), 7.05-6.98 (m, 1H), 2.59 MS (ESI) 214.5 (M⁺). Thismaterial was carried on to the next step without further purification.

EXAMPLE 37 Synthesis of2-[1,2-Dibromo-2-(3-fluorophenyl)ethyl[-6-methyl]pyrazin

2-[(E)-2-(3-Fluorophenyl)ethenyl]-6-methylpyrazine from Example 36 (4.14g, 19.3 mmol) was dissolved in CCl₄ (40 mL). To this solution was addeda solution of bromne (1.2 mL, 23 mmol) in CC₄ (20 mL). The brown mixturewas then heated to 60° C. After 6 h the suspension was treated withsaturated aqueous NaHCO₃ (200 mL) and diluted with ethyl acetate (700mL). The organic layer was washed with 5% aqueous Na₂S₂O₃ (100 mL),brine (100 mL), dried over MgSO₄, filtered, and concentrated in vacuo.The crude product was purified by column chromatography eluting with80:20 hexane:ethyl acetate then 95:5, 94:6, and 90:10 CH₂Cl₂:ethylacetate to afford2-[1,2-dibromo-2-(3-fluorophenyl)ethyl]-6-methylpyrazine (2.97 g, 17%over two steps) as a white solid. This material was carried on to thenext step without further purification.

EXAMPLE 38 Synthesis of 2-[(3-Fluorophenyl)ethynyl]-6-methylpyrazinehydrochloride

2-[1,2-Dibromo-2-(3-fluorophenyl)ethyl]-6-methylpyrazine (2.97 g, 7.94mmol) was dissolved in THF (40 mL), treated with DBU (8.7 mL, 63 mmol),and heated to reflux. After 16 h the reaction mixture was cooled,filtered, concentrated in vacuo, and purified by column chromatographyeluting with 80:20 then 75:25 hexane:ethyl acetate to afford2-[(3-fluorophenyl)ethynyl]-6-methylpyrazine (427 mg, 25% yield). Thismaterial was carried on to the salt formation without furtherpurification.

2-[(3-Fluorophenyl)ethynyl]-6-methylpyrazine (520 mg, 2.45 mmol) wasdissolved in CH₂Cl₂ (3 mL), and the resulting solution was treated withHC₁in diethyl ether (2.7 mL of a 1.0M solution, 2.7 mmol). The mixturewas sonicated, and the solvent decanted. The remaining solid was driedunder high vacuum to afford 2-[(3-fluorophenyl)ethynyl]-6-methylpyrazinehydrochloride (338 mg, 60% yield) as a light yellow solid. M.p. 62-63°C. ¹H NMR (CDCl₃, 300 MHz) Δ8.73 (s, 1H), 8.57 (s, 1H), 7.54-7.35 (m,3H), 7.28-7.20 (m, 3H), 2.84 (s, 3H).

EXAMPLE 39 Synthesis of 1-Chloro-4-(1-cyclohexen-1-yl-3-butyn-2-one

Anhydrous ZnCl₂ (5.0 g, 37 mmol) was dissolved in TBF (25 mL) and thesolution cooled to 0° C. in an ice bath. In another flask1-ethynylcyclohexene (4.3 mL, 36.3 mmol) was dissolved in THF (25 mL),cooled to 0° C. in an ice bath, and treated with n-butyllithium (15.7 mLof a 2.2M solution in hexane, 34.5 mmol). After 20 minutes thecyclohexenylethynyllithium solution was added via cannula to the ZnCl₂solution. After an additional 20 minutes Pd(PPh₃)₄ (620 mg, 0.54 mmol)was added to the alkynylzinc solution. The resulting yellow solution wastreated with chloroacetyl chloride (4.2 mL, 55 mmol) dropwise over 10minutes. After 2 h at 0° C. the reaction mixture was quenched by theaddition of saturated aqueous NH₄Cl (500 mL), and diluted with ethylacetate. The aqueous phase was extracted with ethyl acetate (3.times.200ml) and the combined organic layers were washed with water (200 ml),brine (200 ml), dried over Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo to afford a dark brown oil that was purified bycolumn chromatography eluting with hexane, then 99:1 hexane:ethylacetate to afford 1-chloro-4-(1-cyclohexen-1-yl)-3-buty-n-2-one (4.4 g,67% yield) as an orange oil. ¹H NMR (CDCl₃, 300 MHz) Δ6.56 (m, 1H), 4.23(s, 2H), 2.19 (m, 4H), 1.68-1.62 (m, 4H). MS (EI ionization) 182 (³⁵ClM⁺), 184 (³⁷Cl M⁺). The material was carried on to the next step withoutfurther purification.

EXAMPLE 40 Synthesis of4-(1-Cyclohexen-1-ylethynyl)-2-methyl-1,3-thiazole, p-toluenesulfonicacid salt

1-Chloro-4-(1-cyclohexen-1-yl)-3-butyn-2-one (2.0 g, 11.0 mmol) wasdissolved in DMF (10.0 mL), thioacetarnide (950 mg, 12.6 mmol) wasadded, and the resulting pale brown solution was stirred at ambienttemperature for 64 h. The reaction mixture was diluted with ethylacetate (300 mL), washed with saturated NaHCO₃ solution (300 mL), water(300 mL), brine (300 mL), dried over Na₂SO₄, filtered, and concentratedin vacuo. The residue was dissolved in ethyl acetate, adsorbed ontosilica gel and purified by column chromatography eluting with hexane,99:1 then 98:2 hexane:ethyl acetate to afford4-(1-cyclohexen-1-ylethynyl-)-2-methyl-1,3-thiazole (620 mg, 28% yield)as a yellow powder. 1H NMR (CDCl₃, 300 MHz) Δ7.22 (s, 1H), 6.27-6.24 (m,1H). 2.7 (s, 3H) 2.22-2.12 (m, 4H), 1.68-1.58 (m, 4H).

4-(1-Cyclohexen-1-ylethynyl)-2-methyl-1,3-thiazole (620 mg, 3.1 mmol)was dissolved in ethanol (30 mL) at ambient temperature.p-Toluenesulfonic acid monohydrate (580 mg, 3.1 mmol) was added in oneportion to afford a brown solution. After all of the acid had dissolvedthe reaction mixture was stirred for several minutes and thenconcentrated in vacuo to afford a dark brown oil which solidified underhigh vacuum. The crude material was dissolved in hot ethyl acetate.After cooling to ambient temperature the material was stored in thefreezer for few hours. The supernatant solution was decanted and thecrystalline solids were dried under high vacuum to afford crystalline4-(1-cyclohexen-1-ylethynyl)-2-methyl-1,3-thiazole p-toluenesulfonatesalt (882 mg, 74% yield) as yellow crystals. M.p. 128-129° C. ¹H NMR(CD₃OD, 300 MHz) Δ7.87 (s, 1H), 7.71-7.68 (d, J=9 Hz, 2H), 7.24 (m, 7.21(d, J=9 Hz, 3H), 6.38 (m, 1H), 2.88, (s, 3H), 2.36 (s, 1.68-1.64 (m,4H).

EXAMPLE 41 Synthesis of4-(1-Cyclohexen-1-ylethynyl)-1,3-thiazol-2-ylamne, p-toluenesulfonicacid salt

1-Chloro-4-(1-cyclohexen-1-yl)-3-butyn-2-one (2.0 g, 11 mmol) wasdissolved in DMF (10.0 mL), thiourea (996 mg, 13.1 mmol) was added, andthe resulting pale brown solution was stirred at ambient temperature for16 h. The reaction mixture was diluted with ethyl acetate (200 mL),washed with saturated NaHCO₃ solution (100 mL), water (100 mL), brine(100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Thedark oil was dissolved in ethyl acetate, adsorbed onto silica gel andpurified by column chromatography eluting with 9:1 then 3:1 hexane:ethylacetate to afford 4-(1-cyclohexen-1-ylethynyl)-1,3-thiaz-ol-2-ylam;ne(1.1 g, 49% yield) as an off-white solid. MS (EI ionization) 204 (M⁺).

4-(1-Cyclohexen-1-ylethynyl)-1,3-thiazol-2-ylam;ne (1.1 g, 5.4 mmol) wasdissolved in ethanol (40 mL) at ambient temperature. p-Toluenesulfonicacid monohydrate (1.0 g, 5.4 mmol) was added in one portion to afford abrown solution. After all of the acid had dissolved the reaction mixturewas stirred for several minutes and then concentrated in vacuo to afforda dark brown oil which solidified under high vacuum. The crude materialwas dissolved in hot ethyl acetate. After cooling to ambient temperaturethe material was stored in the freezer. After several hours in thefreezer, the supernatant solution was decanted and the crystallinesolids were dried under high vacuum to afford4-(1-cyclohexen-1-ylethynyl)-1,3-thiazol-2-ylamne p-toluenesulfonatesalt (1.84 g, 87% yield) as off-white powder. M.p. 188-189° C. ¹H NMR(CD₃OD, 300 MHz) Δ7.72-7.69 (d, J=9 Hz, 2H), 7.24-7.22 (d, J=6 Hz, 2H)6.94 (s, 1H), 6.34-6.32 (m, 1H), 2.36 (s, 3H), 2.19-2.15 (m, 4H)1.70-1.61 (m, 4H).

EXAMPLE 42 Synthesis of 2-(1-Cyclohexen-1-ylethynyl)-6-methylpyridine

2-Bromo-6-methyl pyridine (2.0 g, 12 mmol) and CuI (440 mg, 2.3 mmol)were combined in DME (30 mL), and argon gas was bubbled through thesuspension for several minutes to deoxygenate the mixture. Triethylamne(8.0 mL, 58 mmol) and PdCl₂(PPh₃)₂ (814 mg, 1.16 mmol) were added,followed by the dropwise addition of 1-ethynylcyclohexene (1.7 g, 15mmol). The reaction was stirred at ambient temperature overnight. GC/MSshowed no starting 2-bromo-6-methylpyridine remaining. The mixture wasdiluted with ethyl acetate (100 mL), and filtered through Celite.™ Thepad was then thoroughly washed with ethyl acetate and the combinedfiltrates were washed with water (200 mL), brine (200 mL), dried overNa₂SO₄, and filtered. The filtrate was concentrated in vacuo, and theresidue was purified by column chromatography eluting with hexane then99:1, 98:2 hexane:ethyl acetate to afford2-(1-cyclohexen-1-ylethynyl)-6-methylpyridine (1.8 g, 79% yield) as ared oil. ¹H NMR (CDCl₃, 300 MHz) Δ7.51-7.46 (m, 1H), 7.21 (d, J=9 Hz,1H), 7.03 (d, J=9 1H), 6.32-6.29 (m, 1H), 2.53 (s, 3H), 2.24-2.21 (m,2H), 2.14-2.12 (m, 2H), 1.67-1.57 (m, 4H). MS (ESI) 198.1 (M⁺).

EXAMPLE 43 Synthesis of 2-(Cyclohexylethynyl)-6-methylpyridine

2-Bromo-6-methyl pyridine (2.0 g, 11.6 mmol) and Cui (440 mg, 2.3 mmol)were combined in DME (30 mL), and argon gas was bubbled through thesuspension for several minutes to deoxygenate the mixture. Triethylamne(8.0 mL, 58 mmol) and PdCl₂(PPh₃)₂ (814 mg, 1.16 mmol) were added,followed by the dropwise addition of cyclohexylethyne (1.25 g, 11.6mmol). The reaction was stirred at ambient temperature overnight. GC/MSshowed no starting 2-bromo-6-methylpyridine remaining. The mixture wasdiluted with ethyl acetate (100 mL), and filtered through Celite.™ Thepad was then thoroughly washed with ethyl acetate and the combinedfiltrates were washed with water (200 mL), brine (200 mL), dried overNa₂SO₄, and filtered. The filtrate was concentrated in vacuo, and theresidue was purified by column chromatography eluting with hexane then98:2, 96:4 hexane:ethyl acetate to afford2-(cyclohexylethynyl)-6-me-thylpyridine (1.78 g, 77% yield) as a palebrown liquid that partially solidified on standing in the freezer. ¹HNMR (CDCl₃, 300 MHz) Δ7.52-7.46 (m, 1H), 7.20 (d, J=9 Hz, 1H), 7.03 (d,J=9 Hz, 1H), 2.6 (m, 1H), 2.54 (s, 3H), 2.93-2.89 (m, 2H), 1.78-1.73 (m,2H), 1.57-1.54 (m, 3H), 1.36-1.32 (m, 3H). MS (ESI) 200.1 (M⁺+H).

EXAMPLE 44 Synthesis of 3-methyl-6-(pyridin-3-ylethynyl)pyridazine

To the solution of 3-[(trimethylsilyl)ethynyl]pyridine (0.175g, 1.0mmol), 3-chloro-6-methylpyridazine (0.128 g, 1.0 mmol), cupper (I)iodide (0.019 g, 0.1 mmol), triethylamine (0.202 g, 2.1 mmol), in 20 mlEthylene glycol dimethyl ether was addedtetrakis(triphenlyphosphine)palladium (0) (60 mg, 0.052 mmol). Theresult solution was heated to 80° C. after degasing by argon for 5minute, and then Tetrabutylammonium fluoride (2.1 ml, 1M/THF) was addeddropwise. After stirring at 80° C. for 12 hour, the reaction mixture wasquenched with H₂O (30 mL), then extracted with EtOAc (3×30 mL) and thecombined organic extracts washed with brine. The organic phase was driedover Na₂SO₄ and concentrated in vacuo. The crude purified by liquidchromatography on silica gel using an ISCO single channel system(Hexane/EtOAc: 9/1 to 1/9) to give3-methyl-6-(pyridin-3-ylethynyl)pyridazine as brown solid. ¹H NMR (CDCl₃300 MHz) δ 8.875-8.87 (m, 1H), 8.65-8.63 (d, 1H), 7.95-7.93 (d, 1H),7.60-7.58 (dd, 1H), 7.39-7.36 (m, 2H), 2.80 (s, 3H). MS (ESI) 196.10(M⁺+H).

The following examples were prepared using this general procedure.

EXAMPLE 45 3-Methyl-6-(pyridin-3-ylethynyl)pyridazine

8.87 (d, 1H), 8.65-8.63 (d, 1H), 7.95-7.93 (m, 1H), 7.60-7.58 (m, 1H),7.39-7.39 (m, 2H), 2.80 (s, 3H). MS 196.1 (M++H).

EXAMPLE 46 6-(Pyrimidin-2-ylethynyl)-2,3′-bipyridine

9.236-9.229 (d, 1H)), 8.83 (s, 1H), 8.82 (s, 1H), 8.70-8.68 (dd, 1H),8.47-8.43 (m, 1H), 7.89-7.80 (m, 2H), 7.70-7.67 (dd, 1H), 7.47-7.42 (dd,1H), 7.35-7.32 (m, 1H). MS 259.0 (M++H).

EXAMPLE 47 2-[(6-pyridin-3-ylpyrazin-2-yl)ethynyl]pyrimidine

9.39-9.36 (m, 2H), 8.96-8.92 (m, 3H), 8.76-8.74 (dd, 1H), 8.58-8.54 (m,1H). 7.62-7.58 (m, 2H) MS 260.0 (M++H).

EXAMPLE 48 2-[(6-pyrrolidin-1-ylpyridin-3-yl)ethynyl]pyrimidine

8.83-8.82 (d, 2H), 8.25 (d, 1H), 8.09-8.07 (dd, 1H), 7.51-7.49 (m, 1H),7.18-7.16 (d, 1H), 3.66 (m, 4H), 2.18 (m, 4H). MS 251.14 (M++H).

EXAMPLE 49 2-[(6-pyrrolidin-1-ylpyridin-3-yl)ethynyl]pyrazine

8.87 (br, 1H), 8.67 (m, 2H), 8.23 (d, 1H), 8.08-8.06 (dd, 1H), 7.19-7.17(d, 1H), 3.66 (m, 4H), 2.18 (m, 4H). 251.09 (M++H).

EXAMPLE 504-methoxy-2-[(6-pyrrolidin-1-ylpyridin-3-yl)ethynyl]pyrimidine

8.50-8.49 (d, 1H), 8.26 (s, 1H), 8.09-8.07 (m, 1H), 7.19-7.17 (m, 1H),6.93-6.91 (d, 1H), 4.03 (s, 3H), 3.66 (m, 4H), 2.18 (m, 4H). MS 281.09(M++H).

EXAMPLE 51 2-[(5-methoxypyridinium-3-yl)ethynyl]pyrimidin-1-iumdichloride

8.90 (m, 2H), 8.84 (s, 1H), 8.74 (s, 1H), 8.52 (m, 1H), 7.59 (dd, 1H),4.15 (s, 3H). 212.1 (M++H).

EXAMPLE 52 5-(pyrazin-2-ylethynyl)-3,3′-bipyridine

8.88 (m, 4H), 8.73 (m, 1H), 8.66 (m, 1H), 8.59 (m, 1H) MS 259 (M++H).

EXAMPLE 53 5-bromo-2-(pyridin-3-ylethynyl)pyrimidine

8.88 (s, 1h), 8.82 (s, 2H), 8.64-8.62 (m, 1H), 7.35-7.25 (m, 1H). MS 261(M++H).

EXAMPLE 54 5-phenyl-2-(pyridin-3-ylethynyl)pyrimidine

8.99 (s, 2H), 8.91 (s, 1H), 8.64-8.63 (m, 1H), 7.98-7.95 (m, 1H),7.64-7.49 (m, 4H), 7.36-7.32 (m, 1H). MS 258 (M++H).

EXAMPLE 55 5-(3-chlorophenyl)-2-(pyridin-3-ylethynyl)pyrimidine

8.96 (s, 2H), 8.92 (s, 1H), 8.65-8.64 (m, 1H), 7.98-7.95 (m, 1H),7.61-7.60 (m, 1H), 7.50-7.46 (m, 3H), 7.37-7.32 (m 1H). MS 292 (M++H).

EXAMPLE 56 5-[(E)-2-phenylvinyl]-2-(pyridin-3-ylethynyl)pyrimidine

1H NMR (CDCl3, 500 MHz) δ 8.91-8.89 (m, 3H), 8.64-8.63 (m, 1H),7.98-7.94 (m, 1H), 7.57-7.55 (m, 2H), 7.45-7.32 (m, 4H), 7.28-7.27 (d,1H), 7.05-6.99 (m, 1H). MS 284.0 (M++H).

EXAMPLE 57 2-(pyridin-3-ylethynyl)-5-vinylpyrimidine

1H NMR (CDCl3, 500 MHz) δ 8.91-8.90 (d, 1H), 8.80 (s, 2H), 8.64-8.62 (m,1H), 7.97-7.94 (m, 1H), 7.36-7.32 (m, 1H), 6.74-6.64 (m, 1H), 6.03-5.97(d, 1H), 5.61-5.57 (d, 1H). MS 208.1 (M++H).

While the invention has been described in detail with reference tocertain preferred embodiments thereof, it will be understood thatmodifications and variations are within the spirit and scope of thatwhich is described and claimed.

1. A compound selected from:

and enantiomers, diastereomeric isomers or mixtures of any two or morethereof, or pharmaceutically acceptable salts thereof.
 2. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier therefor.